Treatment of allergic rhinitis using a combination of mometasone and olopatadine

ABSTRACT

The present invention relates to a method of treating allergic rhinitis in a subject (e.g., a pediatric human subject) in need thereof comprising nasally administering to the subject an effective amount of a fixed-dose pharmaceutical composition comprising mometasone or its salt and olopatadine or its salt.

This patent application is a continuation application of U.S. patentapplication Ser. No. 15/903,597, filed Feb. 23, 2018, which is acontinuation-in-part application of U.S. patent application Ser. No.15/842,063, filed Dec. 14, 2017, which is a continuation-in-partapplication of U.S. patent application Ser. No. 15/716,661, filed Sep.27, 2017, which is a continuation-in-part of U.S. patent applicationSer. No. 15/691,500, filed Aug. 30, 2017, which is acontinuation-in-part of U.S. patent application Ser. No. 15/636,120,filed Jun. 28, 2017, which is a continuation-in-part of U.S. patentapplication Ser. No. 14/682,001, filed Apr. 8, 2015, which is acontinuation-in-part of U.S. patent application Ser. No. 14/506,122,filed Oct. 3, 2014, which claims the benefit of Indian ProvisionalPatent Application number 3174/MUM/2013, filed Oct. 4, 2013, each ofwhich is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present patent application relates to a method of treating allergicrhinitis in a subject (preferably a human) by administering acombination of mometasone or its salt and olopatadine or its salt.

BACKGROUND OF THE INVENTION

Allergic rhinitis is a medical term for inflammation and irritation ofthe mucous membrane inside the nose. It generally occurs when anallergen such as pollen, dust, or animal dander (particles of shed skinand hair) is inhaled by an individual with a sensitized immune system.Allergic rhinitis may cause additional symptoms such as rhinorrhea(excess nasal secretion), sneezing, nasal itching, nasal congestion andobstruction, coughing, headache, fatigue and malaise. Symptoms may varyin severity between individuals.

Many treatment options are available for treating allergic rhinitis suchas, for example, antihistamines (e.g., cetirizine and loratadine),steroids (e.g., triamcinolone), decongestants, and leukotriene receptorantagonists (e.g., montelukast). These treatments are generallyadministered orally or nasally and some are associated with unpleasanttaste and smell (e.g., Dymista® nasal spray, which is a combination ofazelastine and fluticasone propionate).

Olopatadine hydrochloride, an antihistamine, is chemically described as(Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride, and is disclosed in U.S. Pat. Nos. 4,871,865 and4,923,892. It is commercially available in the United States asPATANASE® Nasal Spray, which contains 0.6% w/v olopatadine (base) in anon-sterile aqueous solution. It is indicated for the relief of thesymptoms of seasonal allergic rhinitis (SAR) in adults and children 6years of age and older. PATANASE® was found to have an onset of actionof 30 minutes after dosing in the environmental exposure unit (Ref:USFDA approved label for Patanase).

Mometasone furoate is a glucocorticosteroid used topically to reduceinflammation of the skin or in the airways. Mometasone furoatemonohydrate is commercially available in the United States as NASONEX®,a nasal spray indicated for (i) the treatment of nasal symptoms ofallergic rhinitis in patients ≥2 years of age, (ii) the treatment ofnasal congestion associated with seasonal allergic rhinitis in patients≥2 years of age, (iii) the prophylaxis of seasonal allergic rhinitis inpatients ≥12 years of age, and (iv) the treatment of nasal polyps inpatients ≥18 years of age. It is available as 50 mcg in a metered-dose,manual pump spray unit containing an aqueous suspension of mometasonefuroate monohydrate equivalent to 0.05% w/w mometasone furoate(calculated on the anhydrous basis).

International Publication No. WO 2011/141929 discloses an aqueous nasalspray solution comprising fluticasone and olopatadine.

U.S. Pat. No. 6,127,353 discloses a pharmaceutical composition ofmometasone furoate monohydrate.

U.S. Pat. Nos. 7,977,376 and 8,399,508 disclose a topical formulation ofolopatadine hydrochloride.

International Publication No. WO 2011/008923 discloses a nasal sprayregimen of olopatadine for children.

International Publication No. WO 1995/020393 discloses the use ofmometasone furoate for treating airway passage and lung diseases.

International Publication No. WO 2010/025236 discloses a combination ofa nasal steroid and a nasal antihistamine for the treatment of viralupper respiratory tract infections, upper respiratory infections, andcommon colds.

Allergic rhinitis is an uncomfortable ailment and affects the quality oflife of allergy sufferers. A fast onset of action would be highlydesirable to provide quick relief from the symptoms of allergicrhinitis. There exists a need for therapies which provide a fast onsetof action, preferably in less than 30 minutes.

SUMMARY OF THE INVENTION

The present invention relates to a fixed dose combination of mometasoneor its salt and olopatadine or its salt and its use for the treatment ofrhinitis in a subject in need thereof. The inventors have surprisinglyfound that mometasone furoate and olopatadine hydrochloride actsynergistically in the treatment of allergic rhinitis and thecombination is more effective and provides better therapeutic value thantreatment with either active ingredient alone.

The inventors have also surprisingly found that nasal administration ofa pharmaceutical composition of mometasone or a salt thereof (such asmometasone furoate) and olopatadine or a salt thereof (such asolopatadine hydrochloride) provides a faster onset of action of reliefof symptoms associated with allergic rhinitis, such as seasonal allergicrhinitis or perennial allergic rhinitis, when compared to olopatadinehydrochloride monotherapy or mometasone fuorate monotherapy. Inparticular, the pharmaceutical composition provides faster relief ofnasal symptoms, such as nasal congestion, rhinorrhea, itching andsneezing. The pharmaceutical composition may also provide a faster onsetof action of ocular symptoms, such as ocular itching, tearing/wateryeyes and ocular redness. The onset of action may be less than 30minutes, such as within about 15 minutes, such as within about 10minutes. In an embodiment, the present invention relates to a method oftreating allergic rhinitis in a subject (e.g., a human) in need thereofcomprising nasally administering to the subject an effective amount of afixed-dose pharmaceutical composition comprising mometasone or its saltand olopatadine or its salt. Preferably, the composition is nasallyadministered as 1 or 2 sprays per nostril of the subject at least oncedaily. Each spray preferably comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60,such as in a weight ratio of from about 1:12 to about 1:53, from about1:13.3 to about 1:50, or from about 1:18 to about 1:40 (based on theequivalent weight of olopatadine free base). In one embodiment, thefixed-dose pharmaceutical composition is a suspension wherein themometasone or its salt is present in particulate form and theolopatadine or its salt is present in dissolved form.

In another embodiment, the present invention relates to a method oftreating allergic rhinitis in a subject (e.g., a human) in need thereofcomprising nasally administering to the subject an effective amount of afixed-dose pharmaceutical composition comprising mometasone furoatemonohydrate and olopatadine hydrochloride. In one preferred embodiment,the composition is nasally administered as 1 or 2 sprays per nostril ofthe subject at least once daily. Each spray of the pharmaceuticalcomposition may comprise olopatadine hydrochloride equivalent to about300 mcg, about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcgof olopatadine, and about 12.5 mcg, about 25 mcg, about 37.5 mcg, about50 mcg, or about 62.5 mcg of mometasone furoate. In one embodiment, eachspray comprises olopatadine hydrochloride equivalent to about 600 mcg ofolopatadine and about 25 mcg of mometasone furoate. In anotherembodiment, each spray comprises olopatadine hydrochloride equivalent toabout 600 mcg of olopatadine and about 50 mcg of mometasone furoate.

Allergic rhinitis in the context of present invention includes, but isnot limited to, inflammation and irritation of the mucous membraneinside the nose, and nasal and/or non-nasal symptoms associatedtherewith. It includes, for example, persistent allergic rhinitis,perennial allergic rhinitis, seasonal allergic rhinitis, chronicrhinitis, rhinitis medicamentosa, vasomotor rhinitis, infectiverhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis,atrophic rhinitis, and gustatory rhinitis. Preferably, the allergicrhinitis is selected from perennial allergic rhinitis, persistentallergic rhinitis, seasonal allergic rhinitis, and nasal and/ornon-nasal symptoms associated therewith.

In the context of the present invention, symptoms associated withrhinitis includes rhinorrhea, nasal congestion, nasal itching, sneezing,itching/burning eyes, tearing/watering eyes, redness of eyes, itching ofears or palate, coughing, ocular pruritus, excess lacrimation, headache,fatigue and malaise.

In another embodiment, of the present invention relates to a method oftreating allergic rhinitis in a subject (e.g., a human) in need thereof,the method comprising nasally administering to the subject an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasoneor its salt and olopatadine or its salt in a weight ratio of about 1:5to about 1:60 or from about 1:12 to about 1:53, wherein (i) thecomposition is nasally administered as 1 or 2 sprays per nostril, onceor twice daily, and (ii) each spray comprises olopatadine hydrochlorideequivalent to about 600 mcg of olopatadine and about 25 mcg to about 50mcg of mometasone furoate. In one embodiment, the composition isadministered for about 1 week. In another aspect of the embodiment, thecomposition is administered for about 2 weeks.

In one embodiment, the total nasal symptoms score (TNSS) of the humansubject is reduced by at least 40%, preferably by at least 50% frombaseline after 1 or 2 weeks treatment. In another embodiment, the totalocular symptom score (TOSS) of the human subject is reduced by at least30%, preferably by at least 40% from baseline after 1 or 2 weekstreatment. In an aspect of the invention, the total nasal symptoms score(TNSS) and the total ocular symptom score (TOSS) can be observed asinstantaneous or reflective or both.

Yet another embodiment is a method of treating symptoms associated withallergic rhinitis in a human subject in need thereof comprising nasallyadministering twice daily, two sprays per nostril of a fixed-dosepharmaceutical composition comprising mometasone or its salt (e.g.,mometasone furoate) and olopatadine its salt (e.g., olopatadinehydrochloride). Each spray may comprise mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60(such as a weight ratio of about 1:12 to about 1:53, about 1:13.3 toabout 1:50, or from about 1:18 to about 1:40) (based on the equivalentweight of olopatadine free base) (for example, each spray comprisesabout 12.5 mcg, about 25 mcg, about 37.5 mcg, about 50 mcg, or about62.5 mcg of mometasone or its salt (such as about 50 mcg mometasonefuroate) and olopatadine hydrochloride equivalent to about 300 mcg,about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg ofolopatadine (such as about 665 mcg olopatadine hydrochloride)). Theadministration may provide relief from one or more symptoms of allergicrhinitis (such as nasal symptoms or ocular symptoms) faster (e.g., anonset of action in less than 30 minutes, such as within about 15minutes, such as within 10 minutes) than nasal administration of themometasone or its salt or the olopatadine or its salt alone. In anotherembodiment, the administration may provide relief from one or moresymptoms of allergic rhinitis (such as nasal symptoms) in a subjectexposed to an environmental exposure chamber (EEC) (such as one withragweed pollen at a concentration of 3500±500 particles/m³ for 6 hours)faster (e.g., an onset of action in less than 15 minutes, such as withinabout 10 minutes) than nasal administration of the mometasone or itssalt or the olopatadine or its salt alone.

Yet another embodiment is a method for providing faster onset of reliefof symptoms associated with allergic rhinitis in a human subject in needthereof comprising nasally administering twice daily, two sprays pernostril of a fixed-dose pharmaceutical composition comprising mometasoneor its salt (e.g., mometasone furoate) and olopatadine its salt (e.g.,olopatadine hydrochloride). This method may provide faster onset ofrelief of one or more symptoms compared to administration of themometasone or its salt alone or olopatadine or its salt alone. Eachspray may comprise mometasone or its salt and olopatadine or its salt ina weight ratio of about 1:5 to about 1:60 (such as a weight ratio ofabout 1:12 to about 1:53, about 1:13.3 to about 1:50, or from about 1:18to about 1:40) (based on the equivalent weight of olopatadine free base)(for example, each spray comprises about 12.5 mcg, about 25 mcg, about37.5 mcg, about 50 mcg, or about 62.5 mcg of mometasone or its salt(such as about 50 mcg mometasone furoate) and olopatadine hydrochlorideequivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750mcg, or about 900 mcg of olopatadine (such as about 665 mcg olopatadinehydrochloride)). The administration may provide relief from one or moresymptoms within 30 minutes, such as within 15 minutes or 10 minutes. Inanother embodiment, the administration may provide relief from one ormore symptoms of allergic rhinitis (such as nasal symptoms) in a subjectexposed to an environmental exposure chamber (EEC) (such as one withragweed pollen at a concentration of 3500±500 particles/m3 for 6 hours)in less than 15 minutes, such as within about 10 minutes.

The human subject may previously been treated with mometasone or itssalt alone or olopatadine or its salt alone. In such human subjects, themethods described herein may include the step of discontinuing treatmentwith the monotherapy of mometasone or its salt or olopatadine or itssalt prior to initiating nasal administration of the fixed dosepharmaceutical composition of mometasone or its salt and olopatadine orits salt.

In one embodiment, the methods herein provide faster onset of action forrelief of nasal symptoms in the subject. In another embodiment, themethods herein provide faster onset of action for relief of ocularsymptoms in the subject.

In one preferred embodiment, the method comprises nasally administeringto a human subject twice daily, two sprays per nostril of a fixed-dosepharmaceutical composition comprising 25 mcg mometasone furoate and 665mcg olopatadine hydrochloride.

In one embodiment, the pharmaceutical composition provides faster onsetof action for relief of nasal symptoms in the subject. In anotherembodiment, the pharmaceutical composition provides faster onset ofaction for relief of ocular symptoms in the subject.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis comprising the step of administering to thesubject a pharmaceutical composition for twice daily nasaladministration of two sprays per nostril, wherein (i) the pharmaceuticalcomposition provides an onset of action within 15 minutes for thetreatment of allergic rhinitis and (ii) each spray of the pharmaceuticalcomposition comprises about 25 mcg of mometasone furoate and about 665mcg of olopatadine hydrochloride.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis comprising the steps of:

(a) prescribing to a subject (e.g., a human subject) a fixed-dosepharmaceutical composition for twice daily nasal administration of twosprays per nostril, wherein the fixed-dose pharmaceutical compositioncomprises mometasone or its salt (such as mometasone furoate) andolopatadine or its salt (such as olopatadine hydrochloride), and eachspray comprises mometasone or its salt and olopatadine or its salt in aweight ratio of about 1:5 to about 1:60 (such as a weight ratio of about1:12 to about 1:53, about 1:13.3 to about 1:50, or from about 1:18 toabout 1:40) (based on the equivalent weight of olopatadine free base)(for example, each spray comprises about 12.5 mcg, about 25 mcg, about37.5 mcg, about 50 mcg, or about 62.5 mcg of mometasone or its salt(such as about 50 mcg mometasone furoate) and olopatadine hydrochlorideequivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750mcg, or about 900 mcg of olopatadine (such as about 665 mcg olopatadinehydrochloride)),

the prescribing being performed in response to (i) marketing of thepharmaceutical composition as (A) providing faster onset of action (suchas an onset of action within less than 30 minutes, such as within 15minutes, such as within 10 minutes) for relief of one or more symptoms(e.g., nasal symptoms) of allergic rhinitis than nasal administration ofmometasone or its salt (such as 25 or 50 mcg mometasone furoate) orolopatadine or its salt (such as 665 mcg olopatadine hydrochloride)alone, (B) providing relief of one or more symptoms of allergic rhinitiswithin 15 minutes (or 30 minutes), and (ii) diagnosis of the humansubject as suffering from allergic rhinitis, or (C) providing fasteronset of action (such as within 15 minutes, such as within about 10minutes) for relief of one or more symptoms (e.g., nasal symptoms) ofallergic rhinitis in subjects exposed to an environmental exposurechamber (EEC) (such as one with ragweed pollen at a concentration of3500±500 particles/m³ for 6 hours) than nasal administration of themometasone or its salt or the olopatadine or its salt alone. (D)providing relief from one or more symptoms of allergic rhinitis (such asnasal symptoms) in subjects exposed to an environmental exposure chamber(EEC) (such as one with ragweed pollen at a concentration of 3500±500particles/m³ for 6 hours) within 15 minutes, such as within about 10minutes; and

(b) administering the prescribed pharmaceutical composition to thesubject. In one preferred embodiment, each spray of the fixed-dosepharmaceutical composition provides 25 mcg mometasone furoate and 665mcg olopatadine hydrochloride.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis (such as seasonal allergic rhinitis or perennialallergic rhinitis) comprising the step of administering to the subject aprescribed fixed-dose pharmaceutical composition for twice daily nasaladministration of two sprays per nostril, where the fixed-dosepharmaceutical composition comprises mometasone or its salt (such asmometasone furoate) and olopatadine or its salt (such as olopatadinehydrochloride), and each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60(such as a weight ratio of about 1:12 to about 1:53, about 1:13.3 toabout 1:50, or from about 1:18 to about 1:40) (based on the equivalentweight of olopatadine free base) (for example, each spray comprisesabout 12.5 mcg, about 25 mcg, about 37.5 mcg, about 50 mcg, or about62.5 mcg of mometasone or its salt (such as about 50 mcg mometasonefuroate) and olopatadine hydrochloride equivalent to about 300 mcg,about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg ofolopatadine (such as about 665 mcg olopatadine hydrochloride)). Thepharmaceutical composition is prescribed in response to (a) marketing ofthe pharmaceutical composition as (A) providing faster onset of action(such as an onset of action within less than 30 minutes, such as within15 minutes, such as within 10 minutes) for relief of symptoms (e.g.,nasal symptoms) of allergic rhinitis than nasal administration ofmometasone or its salt (such as 50 mcg mometasone furoate) orolopatadine or its salt (such as 665 mcg olopatadine hydrochloride)alone or (B) providing relief of one or more symptoms of allergicrhinitis within 15 minutes (or 30 minutes), and (b) a diagnosis of thesubject as suffering from allergic rhinitis. In one preferredembodiment, each spray of the fixed-dose pharmaceutical compositionprovides 25 mcg mometasone furoate and 665 mcg olopatadinehydrochloride.

In one embodiment of any of the methods described herein, the allergicrhinitis is selected from perennial allergic rhinitis, persistentallergic rhinitis, seasonal allergic rhinitis, and nasal and/ornon-nasal symptoms associated therewith. In one preferred embodiment, ofany of the methods described herein, the allergic rhinitis is seasonalallergic rhinitis. In another preferred embodiment, of any of themethods described herein, the allergic rhinitis is perennial allergicrhinitis.

In one embodiment, the subject suffers from persistent allergic rhinitisand is treated for 4 or 6 weeks.

In another embodiment, the subject exhibits a positive skin prick testto an allergen. Alternately, the subject may also exhibit positive bloodtests showing an allergy.

In yet another embodiment, the method involves no significanttreatment-related adverse effects in the subject after 1 or 2 weekstreatment.

In another embodiment, the present invention relates to a method oftreating seasonal allergic rhinitis and/or nasal symptoms associatedwith seasonal allergic rhinitis in a subject (e.g., a human) in needthereof comprising nasally administering to the subject a combination(e.g., synergistic combination) comprising mometasone furoate andolopatadine hydrochloride, wherein the combination is in the form of apharmaceutical composition comprising mometasone furoate and olopatadinehydrochloride in a weight ratio of about 1:5 to about 1:60 or from about1:13.3 to about 1:53.2 (based on the equivalent weight of olopatadinefree base). In one embodiment, the present invention relates to a methodof treating allergic rhinitis in a human in need thereof comprisingnasally administering to the human an effective amount of a fixed-dosepharmaceutical composition comprising mometasone or its salt andolopatadine or its salt, wherein (i) the composition is nasallyadministered as 1 or 2 sprays per nostril of the human at least oncedaily, and (ii) each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60 orfrom about 1:13.3 to about 1:53.2 (based on the equivalent weight ofolopatadine free base). The method may provide reduction in at least onetreatment-related adverse effect (e.g. epistaxis and somnolence)relative to the use of the mometasone or olopatadine alone. For example,the method may provide effective treatment of seasonal allergic rhinitisand/or nasal symptoms associated with seasonal allergic rhinitis in asubject with a reduced incidence of drowsiness and nose bleeds. Inanother embodiment, the method may provide effective treatment ofseasonal allergic rhinitis and/or nasal symptoms associated withseasonal allergic rhinitis in a subject without significant drowsinessand/or inducing nose bleeds.

In another embodiment, the present invention relates to a method oftreating perennial allergic rhinitis and/or nasal symptoms associatedwith perennial allergic rhinitis in a subject (e.g., a human) in needthereof comprising nasally administering to the subject a combination(e.g., synergistic combination) comprising mometasone furoate andolopatadine hydrochloride, wherein the combination is in the form of apharmaceutical composition comprising mometasone furoate and olopatadinehydrochloride in a weight ratio of about 1:5 to about 1:60 or from about1:13.3 to about 1:53.2 (based on the equivalent weight of olopatadinefree base).

In one aspect of this embodiment, each spray comprises about 25 mcg orabout 50 mcg mometasone furoate and olopatadine hydrochloride equivalentto about 600 mcg olopatadine. In one aspect of this embodiment, thepharmaceutical composition is a suspension comprising mometasone or itssalt in particulate form and olopatadine or its salt in solution. In oneaspect of this embodiment, the composition is administered for a periodof at least 1 week as—(i) 1 spray per nostril once daily or twice daily,or (ii) 2 sprays per nostril once daily or twice daily. In yet anotheraspect of this embodiment, the allergic rhinitis is selected fromperennial allergic rhinitis, persistent allergic rhinitis, seasonalallergic rhinitis, and nasal and/or non-nasal symptoms associatedtherewith. In a preferred aspect, the allergic rhinitis is seasonalallergic rhinitis and/or nasal symptoms associated therewith. In yetanother aspect of this embodiment, (i) the total nasal symptoms score(TNSS) of the human is reduced by at least 50% from baseline after 2weeks treatment, and/or (ii) total ocular symptom score (TOSS) of thehuman is reduced by at least 40% from baseline after 2 weeks treatment,and/or (iii) no significant treatment-related adverse effects areobserved in the human after 2 weeks treatment. In one aspect of the saidembodiment, the human exhibits a positive skin prick test to anallergen. In one embodiment, the treatment-related adverse effectsinclude somnolence or epistaxis or a combination thereof.

The fixed-dose pharmaceutical composition comprising mometasone or itssalt and olopatadine or its salt may be administered to the subjectaccording to one of the following regimens:

a) the composition is nasally administered as 1 spray per nostril oncedaily for a period of at least 1 week;

b) the composition is nasally administered as 2 sprays per nostril oncedaily for a period of at least 1 week;

c) the composition is nasally administered as 1 spray per nostril twicedaily for a period of at least 1 week;

d) the composition is nasally administered as 2 sprays per nostril twicedaily for a period of at least 1 week;

e) the composition is nasally administered as 1 spray per nostril oncedaily for a period of 2 weeks;

f) the composition is nasally administered as 2 sprays per nostril oncedaily for a period of 2 weeks;

g) the composition is nasally administered as 1 spray per nostril twicedaily for a period of 2 weeks; or

h) the composition is nasally administered as 2 sprays per nostril twicedaily for a period of 2 weeks.

In another embodiment of any of the methods described herein, thesubject is a pediatric subject (e.g., ≥2 to <12 years of age, such as ≥6to <12 years of age or ≥6 months to <6 years of age) and the fixed-dosepharmaceutical composition is nasally administered 1 spray per nostriltwice daily. In one embodiment, each spray of the fixed-dosepharmaceutical composition provides 665 mcg olopatadine hydrochlorideand 25 mcg mometasone furoate (e.g., with the formulation of Example 9).In yet another embodiment, the composition is nasally administered for aperiod of at least 1 week, such as for a period of at least 2 weeks, fora period of at least 4 weeks, for a period of at least 8 weeks or for aperiod of at least 12 weeks. In one embodiment, the subject is 2 tounder 12 years of age. In another embodiment, the subject is 6 to under12 years of age. In yet another embodiment, the subject is 2 to under 6years of age.

Yet another embodiment is a method of treating symptoms associated withallergic rhinitis in a pediatric human subject (e.g., ≥2 to <12 years ofage, such as ≥6 to <12 years of age or ≥6 months to <6 years of age) inneed thereof comprising twice daily nasal administration of a singledose of a pharmaceutical composition comprising mometasone furoate andolopatadine hydrochloride, where a single dose of the compositionprovides about 1330 mcg olopatadine hydrochloride and about 50 mcgmometasone furoate. In one preferred embodiment, a single dose comprisesone spray per nostril of a pharmaceutical composition, where each sprayprovides 665 mcg olopatadine hydrochloride and 25 mcg mometasone furoate(e.g., with the formulation of Example 9). The allergic rhinitis can be,for example, seasonal allergic rhinitis or perennial allergic rhinitis.In one embodiment, the subject is 2 to under 12 years of age. In anotherembodiment, the subject is 6 to under 12 years of age. In yet anotherembodiment, the subject is 2 to under 6 years of age.

Yet another embodiment is a method of treating symptoms associated withallergic rhinitis in a pediatric human subject (e.g., ≥2 to <12 years ofage, such as ≥6 to <12 years of age or ≥6 months to <6 years of age) inneed thereof comprising nasally administering twice daily, one spray pernostril of a fixed-dose pharmaceutical composition comprising mometasonefuroate and olopatadine hydrochloride, where each spray provides 665 mcgolopatadine hydrochloride and 25 mcg mometasone furoate (e.g., with theformulation of Example 9). The allergic rhinitis can be, for example,seasonal allergic rhinitis or perennial allergic rhinitis. In oneembodiment, the subject is 2 to under 12 years of age. In anotherembodiment, the subject is 6 to under 12 years of age. In yet anotherembodiment, the subject is 2 to under 6 years of age.

In another embodiment, the present invention relates to a method oftreating seasonal allergic rhinitis and/or nasal symptoms associatedwith seasonal allergic rhinitis in a human in need thereof comprisingnasally administering to the human a combination (e.g., synergisticcombination) comprising mometasone furoate and olopatadinehydrochloride, wherein the combination is in the form of apharmaceutical composition comprising mometasone furoate in particulateform and olopatadine hydrochloride in solution in a weight ratio ofabout 1:13.3 to about 1:53.2 (based on the equivalent weight ofolopatadine free base), and wherein the composition is administered as 1or 2 sprays per nostril of the human, at least once daily for a periodof at least 1 week wherein the method provides reduction of at least onetreatment-related adverse effect.

In one aspect of this embodiment, the composition is administered oncedaily or twice daily for a period of 2 weeks. In another aspect of thisembodiment, each spray comprises about 25 mcg or about 50 mcg ofmometasone furoate and about 665 mcg of olopatadine hydrochloride. Inyet another aspect of this embodiment, (i) the total nasal symptomsscore (TNSS) of the human is reduced by at least 50% from baseline after2 weeks treatment, and/or (ii) total ocular symptom score (TOSS) of thehuman is reduced by at least 40% from baseline after 2 weeks treatment,and/or (iii) no significant treatment-related adverse effects areobserved in the human after 2 weeks treatment. In one aspect of the saidembodiment, the human exhibits a positive skin prick test to anallergen. Preferably, the treatment-related adverse effects includesomnolence or epistaxis or a combination thereof.

In an aspect of the invention, the fixed-dose pharmaceutical compositionmay be administered for a period of about 1 week, 2 weeks, 4 weeks, 6weeks or 8 weeks. Preferably, the fixed-dose pharmaceutical composition,is administered as 1 or 2 sprays per nostril of the subject (e.g., ahuman), once daily or twice daily for a period of 1 week or 2 weeks. Inanother aspect of the embodiment, each spray of the compositioncomprises olopatadine hydrochloride equivalent to about 600 mcg ofolopatadine and about 25 mcg to about 50 mcg of mometasone furoate.Preferably, each spray of the composition comprises about 665 mcg ofolopatadine hydrochloride (equivalent to about 600 mcg of olopatadine)and about 25 mcg or about 50 mcg of mometasone furoate. In yet anotheraspect, the composition does not have unpleasant odor and taste. In yetanother aspect of the embodiment, the total nasal symptoms score (TNSS)of the human subject is reduced by at least 40% or at least 50% frombaseline after 1 or 2 weeks treatment. In yet another aspect of theembodiment, the total ocular symptom score (TOSS) of the human isreduced by at least 30% or at least 40% from baseline after 1 or 2 weekstreatment. In yet another aspect of the embodiment, the said methodprovides reduction in one or more treatment-related adverse effects.Preferably, the treatment-related adverse effects include somnolence orepistaxis or a combination thereof. In yet another aspect of theembodiment, the human subject is a patient exhibiting a positive skinprick test to an allergen.

In one aspect the present invention relates to the use of mometasone orits salt and olopatadine or its salt in a weight ratio of about 1:5 toabout 1:60 or from about 1:12 to about 1:53 for the manufacture of afixed-dose pharmaceutical composition of the invention for the treatmentof allergic rhinitis in a subject (e.g., a human) in need thereof. In anaspect, the fixed-dose pharmaceutical composition is a suspensionwherein mometasone or its salt is present in particle form (e.g., havinga mean particle size of from about 1 to about 20 μm, or from about 1 toabout 15 μm) and olopatadine or its salt is present in dissolved form.In yet another aspect the composition does not have unpleasant odor andtaste.

In a separate embodiment the present invention relates to a method ofreducing symptoms associated with rhinitis in a subject (e.g. a human)in need thereof, the method comprising nasally administering to thesubject an effective amount of a fixed dose pharmaceutical compositioncomprising mometasone or its salt and olopatadine or its salt in aweight ratio of about 1:5 to about 1:60 or from about 1:12 to about 1:53for about 1 or 2 weeks.

In yet another embodiment, the present invention relates to a method ofreducing symptoms associated with allergic rhinitis in a human in needthereof comprising nasally administering to the human an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasoneor its salt and olopatadine or its salt, wherein (i) the composition isnasally administered as 1 or 2 sprays per nostril of the human at leastonce daily, and (ii) each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60 orfrom about 1:12 to about 1:53 for about 1 or 2 weeks (based on theequivalent weight of olopatadine free base) and wherein the compositionis administered as 1 or 2 sprays per nostril of the human, at least oncedaily for a period of at least 1 week, wherein the method providesreduction of at least one adverse event. In one aspect of thisembodiment, each spray comprises about 25 mcg or about 50 mcg mometasonefuroate and olopatadine hydrochloride equivalent to about 600 mcgolopatadine. In one aspect of this embodiment, the pharmaceuticalcomposition is a suspension comprising mometasone or its salt inparticulate form and olopatadine or its salt in solution. In one aspectof this embodiment, the composition is administered for a period of atleast 1 week as—(i) 1 spray per nostril once daily or twice daily, or(ii) 2 sprays per nostril once daily or twice daily. In yet anotheraspect of this embodiment, the allergic rhinitis is selected fromperennial allergic rhinitis, persistent allergic rhinitis, seasonalallergic rhinitis, and nasal and/or non-nasal symptoms associatedtherewith. In a preferred aspect, the allergic rhinitis is seasonalallergic rhinitis and/or nasal symptoms associated therewith. In yetanother aspect of this embodiment, (i) the total nasal symptoms score(TNSS) of the human is reduced by at least 50% from baseline after 2weeks treatment, and/or (ii) total ocular symptom score (TOSS) of thehuman is reduced by at least 40% from baseline after 2 weeks treatment,and/or (iii) no significant treatment-related adverse effects areobserved in the human after 2 weeks treatment. In one aspect of the saidembodiment, the human exhibits a positive skin prick test to anallergen. In one aspect of the said embodiment, the symptoms includesrhinorrhea, nasal congestion, nasal itching, sneezing, itching/burningeyes, tearing/watering eyes, redness of eyes, itching of ears or palate,coughing, ocular pruritus, excess lacrimation, headache, fatigue andmalaise. In yet another aspect of the embodiment, the treatment-relatedadverse effects include somnolence or epistaxis or a combinationthereof.

Another embodiment relates to a method of reducing eosinophil count inthe nasal lavage of a subject by nasally administering an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasoneor its salt and olopatadine or its salt in a weight ratio of about 1:5to about 1:60 (based on the equivalent weight of olopatadine free base),wherein the method provides a greater reduction in eosinophil count thanthat provided by mometasone or its salt or olopatadine or its salt whenadministered as a monotherapy. The eosinophil count can be measured byany known technique, such as with a hemocytometer.

Yet another embodiment relates to a method of reducing total cell countin the nasal lavage by nasally administering an effective amount of afixed-dose pharmaceutical composition comprising mometasone or its saltand olopatadine or its salt in a weight ratio of about 1:5 to about 1:60(based on the equivalent weight of olopatadine free base) wherein themethod provides a greater reduction in total cell count than thatprovided by mometasone or its salt or olopatadine or its salt whenadministered as a monotherapy.

In another aspect, the present invention relates to a stable fixed dose,aqueous pharmaceutical composition for nasal administration to a human.The composition comprises mometasone or its salt and olopatadine or itssalt. The pharmaceutical composition may be contained within a containersuitable for nasal administration. In one embodiment, the pharmaceuticalcomposition is contained within a spray bottle (such as a sprayer). Thespray bottle may include a container for storing the pharmaceuticalcomposition and a pump for spraying the pharmaceutical compositionintranasally. In one embodiment, the container is capable of storing 30,56, 60, or 120, or 240 doses. For example, a container storing 240 dosescan provide a 1 month supply of the pharmaceutical composition (2 spraysper nostril twice daily (8 sprays per day) for 30 days). A containerstoring 56 doses can provide a 1 week supply of the pharmaceuticalcomposition (2 sprays per nostril twice daily (8 sprays per day) for 7days). In one embodiment, the container may be suitable for containing9-10 mL (e.g., 9 mL or 56 doses), 18-19 mL of the pharmaceuticalcomposition (e.g., 18 mL or 120 doses), or 29-30 mL (e.g., 29 mL or 240doses) of the pharmaceutical composition.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administration toa human, where the composition comprises about 0.001% w/w to about0.075% w/w mometasone or its salt and about 0.5% w/w to about 0.8% w/wolopatadine or its salt. The pharmaceutical composition may be in theform of a solution or a suspension, but preferably the composition is inthe form of a suspension (more preferably, a single phase suspension),wherein mometasone or its salt is present in particle form andolopatadine or its salt is present in dissolved form. In one aspect, themometasone or its salt and olopatadine or its salt are present in aweight ratio of about 1:3 to about 1:106, or from about 1:5 to about1:53, or preferably from about 1:5 to about 1:36.

The composition preferably also includes a hydrocolloid. In oneembodiment, the composition is a suspension and includes a hydrocolloidin a sufficient amount to prevent or inhibit phase separation (i.e.,separation of the particles and solution) after 3 or 6 months of storageat 25±2° C. and 60%±5% relative humidity (RH) or at 40±2° C. and 75%±5%RH. In one embodiment, the aqueous pharmaceutical composition is asingle phase suspension which remains a single phase suspension evenafter 3 or 6 months of storage at 25±2° C. and 60%±5% RH or at 40±2° C.and 75%±5% RH.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administration toa human, where the composition comprises about 0.001% w/w to about0.075% w/w mometasone furoate monohydrate and about 0.5 w/w to about0.8% w/w olopatadine hydrochloride.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid which includescarboxymethylcellulose sodium and xanthan gum. The hydrocolloid may bepresent at a concentration of at least about 0.1% w/w of thecomposition.

One embodiment is a stable fixed dose, aqueous pharmaceutical suspensioncomposition (e.g., contained in a container) for nasal administration toa human, comprising about 0.025% w/w to about 0.05% w/w mometasonefuroate, about 0.6% w/w to about 0.7% w/w olopatadine hydrochloride anda hydrocolloid, where the hydrocolloid is xanthan gum. The xanthan gummay be present at a concentration of at least about 0.1% w/w, orpreferably between about 0.1% w/w to about 3% w/w of the composition.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid, where the hydrocolloid comprisessodium carboxymethyl cellulose. The sodium carboxymethyl cellulose maybe present at a concentration of at least about 0.1% w/w, or preferablybetween about 0.1% w/w to about 3% w/w of the composition.

Yet another embodiment is a stable fixed dose aqueous pharmaceuticalcomposition in the form of suspension (e.g., contained in a container)for nasal administration to a human, comprising mometasone or itspharmaceutically acceptable salt, olopatadine or its pharmaceuticallyacceptable salt, a hydrocolloid at a concentration of at least about0.1% w/w of the composition and a pharmaceutical acceptable excipient.

Suitable pharmaceutical acceptable excipients include, but are notlimited to, chelating agents, preservatives, buffers, surfactants,isotonicity agents, taste masking agents, antioxidants, humectants, pHadjusting agents, and mixtures thereof.

In one embodiment, the pharmaceutical composition has a pH between about3.3 and about 4.1, or between about 3.5 and about 3.9, or between about3.5 to about 3.7. The inventors discovered that the olopatadinehydrochloride crystallizes out of the fixed dose combination aqueoussuspension at a pH of 5 to 5.5. The olopatadine hydrochloride, however,remains dissolved in the aqueous suspension at a pH of about 3.3 toabout 4.1.

The aqueous pharmaceutical composition preferably is substantially freeof crystals of olopatadine hydrochloride. In one embodiment, the aqueouspharmaceutical composition contains less than 2%, less than 1%, lessthan 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition. In another embodiment, the aqueouspharmaceutical composition is substantially free of crystals ofolopatadine hydrochloride after 3 or 6 months of storage at 25±2° C. and60%±5% RH or at 40±2° C. and 75%±5% RH. In yet another embodiment, theaqueous pharmaceutical composition contains less than 2%, less than 1%,less than 0.5%, less than 0.2%, or less than 0.1% of crystallineolopatadine hydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 3 or 6 months of storage at25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5% RH.

The osmolality of the pharmaceutical composition may range between about200 mOsm/kg to about 400 mOsm/kg, or about 250 mOsm/kg to about 350mOsm/kg.

The viscosity of the pharmaceutical composition may range from about 10cps to about 200 cps or preferably from about 20 cps to about 150 cps.In one embodiment, the composition has a viscosity of from about 60 toabout 150 cps, such as from about 90 to about 150 cps or from about 100to about 150 cps. In another embodiment, the composition has a viscosityof from about 20 to about 60 cps.

In yet another aspect, the pharmaceutical composition is in the form ofsuspension and contains mometasone furoate in particles having a meanparticle size in the range of from about 1 μm to about 20 μm, orpreferably from about 1 μm to about 15 μm. In an aspect, the suspensionpharmaceutical composition of the present invention has mean particlesize of less than 15 μm when determined by microscopy technique.

In yet another aspect, the pharmaceutical composition, upon nasaladministration (e.g., as a nasal spray) of a dose equivalent to 200 mcgof mometasone or its salt to a human, results in (a) an area under thecurve (AUC)_(0-∞) for mometasone or its salt of about 50 pg·hr/mL toabout 140 pg·hr/mL, preferably from about 68 pg·hr/mL to about 124pg·hr/mL, (b) a C_(max) for mometasone or its salt of about 6.5 pg/mL toabout 16 pg/ml, preferably from about 8.6 pg/mL to about 12.9 pg/ml, (c)a T_(max) for mometasone or its salt of about 15 minutes to about 120minutes, or (d) any combination of any of the foregoing. In yet anotheraspect, the pharmaceutical composition, upon nasal administration (e.g.,as a nasal spray) of a dose equivalent to 2400 mcg of olopatadine or itssalt to a human, results in (a) an AUC_(0-∞) for olopatadine or its saltof about 42.5 ng·hr/mL to about 116.5 ng·hr/mL, preferably from about56.7 ng·hr/mL to about 99.8 ng·hr/mL, (b) a C_(max) for olopatadine orits salt of about 10.3 ng/mL to about 24.1 ng/ml, preferably from about13.8 ng/mL to about 20.7 ng/ml, (c) a T_(max) of about 15 minutes toabout 120 minutes, or (d) any combination of any of the foregoing.

In yet another aspect, the pharmaceutical composition, upon nasaladministration (e.g., as a nasal spray) of a dose equivalent to 100 mcgof mometasone or its salt (e.g., mometasone furoate) to a human for thefirst time, results in (a) an area under the curve (AUC)_(tau) formometasone or its salt of about 12 pg·hr/mL to about 73 pg·hr/mL,preferably from about 20 pg·hr/mL to about 36 pg·hr/mL, (b) a C_(max)for mometasone or its salt of about 3 pg/mL to about 13 pg/ml,preferably from about 5 pg/mL to about 9 pg/ml, (c) a T_(max) formometasone or its salt of about 15 minutes to about 120 minutes, or (d)any combination of any of the foregoing. In yet another aspect, thepharmaceutical composition, upon nasal administration (e.g., as a nasalspray) of a dose equivalent to 100 mcg of mometasone or its salt (e.g.,mometasone furoate) to a human at steady state (e.g., after 8 days oftwice daily administration of 100 mcg of mometasone or its salt),results in (a) an area under the curve (AUC)_(tau) for mometasone or itssalt of about 26 pg·hr/mL to about 124 pg·hr/mL, preferably from about40 pg·hr/mL to about 80 pg·hr/mL, (b) a C_(max) for mometasone or itssalt of about 4 pg/mL to about 16 pg/ml, preferably from about 8 pg/mLto about 12 pg/ml, (c) a T_(max) for mometasone or its salt of about 15minutes to about 120 minutes, or (d) any combination of any of theforegoing.

In yet another aspect, the pharmaceutical composition, when delivered asa nasal spray has spray characteristics comprising a spray patternhaving a longest axis of about 15-75 mm, a shortest axis of about 10-65mm, and an ellipticity of about 1-2.

Another embodiment is a stable fixed dose pharmaceutical composition inthe form of a suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises xanthan gumat a concentration of about 0.3% w/w of the composition, wherein thecomposition has a pH between about 3.5 to about 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical compositionin the form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises sodiumcarboxymethyl cellulose at a concentration of about 0.5% w/w of thecomposition, wherein the composition has a pH between about 3.5 to about3.9.

In a further embodiment, the stable fixed dose, aqueous pharmaceuticalcomposition is contained in a sprayer, and on delivering a spray of thecomposition to a human nose results in a spray pattern having a longestaxis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of1-2.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 50 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 25 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

In an embodiment, the present invention relates to a stable fixed dosepharmaceutical aqueous suspension composition (e.g., contained in acontainer) for nasal administration to a human, where the compositioncomprises (1) about 0.025% w/w mometasone furoate monohydrate, (2) about0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid selected fromabout 0.3% w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulosesodium (4) about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/wsodium chloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94%w/w sodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate80.

Another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 1% w/w to about 1.2% w/w mixture of microcrystalline celluloseand carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 1% w/w to about 1.2% w/w mixture of microcrystalline celluloseand carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable suspension suitable for nasaladministration to a human, comprising (a) an aqueous solvent, (b)particles of mometasone furoate suspended in the solvent, the particleshaving a mean particle size of from about 1 to about 20 μm, (c)olopatadine hydrochloride dissolved in the solvent, and (d) ahydrocolloid, the suspension having a viscosity in the range of about 20cps to about 150 cps. In one preferred embodiment, the suspension has apH of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg toabout 350 mOsm/kg. In one embodiment, the suspension further comprises achelating agent, a preservative, a buffer, a surfactant, an isotonicityagent, and optionally a pH adjusting agent.

Preferably, the suspensions of the present invention have only one phase(i.e., they are preferably a single phase suspension).

In a further embodiment, the present invention relates to a stable fixeddose, aqueous pharmaceutical composition (e.g., contained in acontainer) for nasal administration comprising about 0.025% w/w to about0.05% w/w mometasone or its salt and about 0.5 w/w to about 0.8% w/wolopatadine or its salt for the treatment of rhinitis in a human in needthereof.

Any of the aforementioned pharmaceutical compositions comprisingmometasone or a salt thereof and olopatadine (or a salt thereof may beused in the aforementioned methods, such as method of treating allergicrhinitis.

In a further embodiment, the present invention relates to a kitcomprising a stable fixed dose, aqueous pharmaceutical compositioncontained in a container, for nasal administration and a package insertcontaining instructions about the use of the pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 50 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to50 μg olopatadine base) on the sneezing response in guinea pigs asdescribed in Example 1.

FIG. 2 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 50 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to50 μg olopatadine base) on total cell count in the nasal lavage ofguinea pigs as described in Example 1.

FIG. 3 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 50 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to50 μg olopatadine base) on the number of eosinophils in the nasal lavageof guinea pigs as described in Example 1.

FIG. 4 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 120 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to120 μg olopatadine base) on the number of eosinophils in the nasallavage of guinea pigs as described in Example 2.

FIG. 5 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 120 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to120 μg olopatadine base) on the total cell count in the nasal lavage ofguinea pigs as described in Example 2.

FIG. 6 is a bar graph depicting the effect of a saline control,ovalbumin control, olopatadine hydrochloride (equivalent to 120 μgolopatadine base), mometasone furoate (10 μg), and a combination ofmometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to120 μg olopatadine base) on the sneezing response in guinea pigs asdescribed in Example 2.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein are defined as follows. If a definition set forthin the present application and a definition set forth earlier in aprovisional application from which the present applications claimspriority are in conflict, the definition in the present applicationshall control the meaning of the terms.

The “onset of action” is the point at which patients might reasonablyexpect to see a meaningful decrease in their allergic rhinitis symptoms(such as a meaningful decrease in reflective total nasal symptom score(rTNSS), instantaneous total nasal symptom score (iTNSS) or reflectivetotal ocular symptom score (rTOSS)). Statistically, it is the first timepoint after initiation of treatment when the drug demonstrates a changegreater than the placebo treatment from baseline in the primary efficacyendpoint. This statistically significant difference between drug andplacebo is maintained for some period (e.g., for 4 hours) from thispoint onward. See “Guidance for Industry, Allergic Rhinitis: ClinicalDevelopment Programs for Drug Products”, U.S. Department of Health andHuman Services, Food and Drug Administration, Center for Drug Evaluationand Research (CDER), April 2000.

The term “faster onset of action” refers, in one embodiment, to astatistically significant faster reduction in one or more parametersassociated with the treatment of allergic rhinitis in a subject, such asa statistically significant faster reduction in reflective total nasalsymptom score (rTNSS), instantaneous total nasal symptom score (iTNSS)or reflective total ocular symptom score (rTOSS) of the subject.

The term “advertising” refers to notifying, informing, and/or apprisingone or more individuals of information (e.g., the efficacy or time foronset of action of a pharmaceutical product for treating or reducing anindication), such as by mass media, including, but not limited to,newspaper, magazine, and internet advertisements, televisioncommercials, and billboard signs. The term “advertising” as used hereinalso includes including a statement that the pharmaceutical product cantreat or reduce the indication in the labeling for the pharmaceuticalproduct.

The term “marketing” refers to the act or process of selling a product,including, but not limited to, any offer for sale or sale of a product,as well as advertising.

The term “effective amount” or “therapeutically effective amount”denotes an amount of an active ingredient that, when administered to asubject for treating allergic rhinitis, produces an intended therapeuticbenefit in a subject. The term “active ingredient” (used interchangeablywith “active” or “active substance” or “drug”) as used herein includesmometasone or its salt and olopatadine or its salt.

By “salt” or “pharmaceutically acceptable salt”, it is meant those saltsand esters which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, and allergic response, commensuratewith a reasonable benefit to risk ratio, and effective for theirintended use. Representative acid additions salts include, but are notlimited to, hydrochloride, hydrobromide, sulphate, bisulphate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate,fumarate, furoate, succinate, tartrate, ascorbate, glucoheptonate,lactobionate, and lauryl sulphate salts. Representative alkali oralkaline earth metal salts include, but are not limited to, sodium,calcium, potassium and magnesium salts. Preferably, the mometasone saltis mometasone furoate (e.g., mometasone furoate monohydrate) and theolopatadine salt is olopatadine hydrochloride.

As used herein, the term “mometasone and its salt” also includeshydrates of mometasone and its salts, such as a monohydrate, for examplemometasone furoate monohydrate.

All references to the weight of, or a weight ratio including,“olopatadine or its salt” or “olopatadine or its salts” are based on theequivalent weight of olopatadine free base, unless otherwise specified.

The term “treating” or “treatment” as used herein also covers theprophylaxis, mitigation, prevention, amelioration, or suppression of adisorder.

The term “synergistic” or “synergy” as used herein refers to acombination exhibiting an effect greater than would be expected from thesum of the effects of the individual components of the combinationalone. The term “synergistic” or “synergy” with regard to thecombination of mometasone or its salt with olopatadine or its salt whichis used in the treatment allergic rhinitis (for example, in the form ofa pharmaceutical composition, a combination product or a kit accordingto the invention) refers to an efficacy for the treatment of theallergic rhinitis that is greater than would be expected from the sum oftheir individuals effects. The advantages for the synergisticcombinations of the present invention include, but are not limited to,exhibiting enhanced efficacy compared to each of the ingredients whenused alone, lowering the required dose of one or more of the activeingredients of the combination, reducing the side effects of one or moreof the active compounds of the combination and/or rendering one or moreof the active ingredients more tolerable to the subject in need oftreatment of the allergic rhinitis.

By “pharmaceutically acceptable excipients”, it is meant any of thecomponents of a pharmaceutical composition other than the actives andwhich are approved by regulatory authorities or are generally regardedas safe for human or animal use.

The term “subject” includes mammals like humans and other animals, suchas domestic animals (e.g., household pets including cats and dogs) andnon-domestic animals (such as wildlife). Preferably, the subject is ahuman. The human patient can be of any age. In one embodiment, the humansubject is at least 2 years of age, at least 12 years of age, or atleast 18 years of age. In another embodiment, the human subject is 18 to65 years of age.

The term “allergic rhinitis” as used herein refers to an allergic and/orinflammatory disease of nasal mucosa, and includes, but is not limitedto, inflammation and irritation of the mucous membrane inside the nose,and nasal and/or non-nasal symptoms associated therewith. Typically theallergic rhinitis includes persistent allergic rhinitis, perennialallergic rhinitis, seasonal allergic rhinitis, chronic rhinitis,rhinitis medicamentosa, vasomotor rhinitis, infective rhinitis,autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis, atrophicrhinitis, and gustatory rhinitis. Preferably, the allergic rhinitisincludes perennial allergic rhinitis, persistent allergic rhinitis,seasonal allergic rhinitis, and nasal and/or non-nasal symptomsassociated therewith. More preferably, the allergic rhinitis includesseasonal allergic rhinitis, and nasal and/or non-nasal symptomsassociated therewith.

In the context of present invention, the nasal and/or non-nasal symptomsassociated with allergic rhinitis include, for example, sneezing, nasalitching, rhinorrhea (runny nose or excess nasal secretion), nasalcongestion, coughing, ocular pruritis, excess lacrimation, headache,fatigue, and malaise.

Methods of Treatment

The present invention relates to use of a fixed dose combination ofmometasone or its salt and olopatadine or its salt for the treatment ofallergic rhinitis in a subject in need thereof. The inventors havesurprisingly found that mometasone furoate and olopatadine hydrochlorideact synergistically in the treatment of allergic rhinitis and theircombination is more effective and provides better therapeutic value thantreatment with either active ingredient alone.

In an embodiment, the present invention relates to a method of treatingallergic rhinitis in a subject (e.g., a human) in need thereofcomprising nasally administering to the subject, an effective amount ofa fixed-dose pharmaceutical composition comprising mometasone or itssalt and olopatadine or its salt. Preferably, the composition is nasallyadministered as 1 or 2 sprays per nostril of the subject at least oncedaily. Each spray may comprise mometasone or its salt and olopatadine orits salt in a weight ratio of about 1:5 to about 1:60, from about 1:10to about 1:55 or from about 1:12 to about 1:53 or from about 1:13.3 toabout 1:50. Preferably, the weight ratio of mometasone or its salt toolopatadine or its salt ranges from about 1:18 to about 1:40 or fromabout 1:24 to about 1:26.6. In an embodiment, the fixed-dosepharmaceutical composition is a suspension wherein mometasone or itssalt is present in particulate form and the olopatadine or its salt ispresent in dissolved form.

Another embodiment relates to a method of treating allergic rhinitis ina subject (e.g., a human) in need thereof comprising nasallyadministering to the subject an effective amount of a fixed-dosepharmaceutical composition comprising mometasone furoate monohydrate andolopatadine hydrochloride. The composition may be nasally administeredas 1 or 2 sprays per nostril of the subject at least once daily. Eachspray of the pharmaceutical composition may comprise olopatadinehydrochloride equivalent to about 300 mcg, about 450 mcg, about 600 mcg,about 750 mcg, or about 900 mcg of olopatadine, and about 12.5 mcg,about 25 mcg, about 37.5 mcg, about 50 mcg, or about 62.5 mcg ofmometasone furoate. In one embodiment, each spray comprises olopatadinehydrochloride equivalent to about 600 mcg of olopatadine and about 25mcg of mometasone furoate. In another embodiment, each spray comprisesolopatadine hydrochloride equivalent to about 600 mcg of olopatadine andabout 50 mcg of mometasone furoate. Preferably, each spray comprisesabout 665 mcg of olopatadine hydrochloride (equivalent to about 600 mcgof olopatadine) and about 25 mcg or about 50 mcg of mometasone furoate.

Allergic rhinitis in the context of present invention includes, but isnot limited to, inflammation and irritation of the mucous membraneinside the nose, and nasal and/or non-nasal symptoms associatedtherewith. It includes, for example, persistent allergic rhinitis,perennial allergic rhinitis, seasonal allergic rhinitis, chronicrhinitis, rhinitis medicamentosa, vasomotor rhinitis, infectiverhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced rhinitis,atrophic rhinitis, and gustatory rhinitis. Preferably, the allergicrhinitis is selected from perennial allergic rhinitis, persistentallergic rhinitis, seasonal allergic rhinitis, and nasal and/ornon-nasal symptoms associated therewith.

In the context of the present invention, symptoms associated withrhinitis includes rhinorrhea, nasal congestion, nasal itching, sneezing,itching/burning eyes, tearing/watering eyes, redness of eyes, itching ofears or palate, coughing, ocular pruritus, excess lacrimation, headache,fatigue and malaise.

In another embodiment, the present invention relates to a method oftreating allergic rhinitis in a subject in need thereof comprisingnasally administering to the human, a fixed-dose pharmaceuticalcomposition comprising mometasone or its salt and olopatadine or itssalt in a weight ratio of about 1:5 to about 1:60 or from about 1:12 toabout 1:53 or from about 1:13.3 to about 1:50, or from about 1:18 toabout 1:40, wherein the composition is nasally administered as 1 or 2sprays per nostril, once or twice daily. Each spray may compriseolopatadine hydrochloride equivalent to about 600 mcg of olopatadine andabout 25 mcg to about 50 mcg of mometasone furoate. In an aspect of theembodiment, the composition is administered for about 1 week. In anotheraspect of the embodiment, the composition is administered for about 2weeks.

In one embodiment, the total nasal symptoms score (TNSS) of the humansubject is reduced by at least 40%, preferably by at least 50% frombaseline after 1 or 2 weeks treatment. In another embodiment, the totalocular symptom score (TOSS) of the human subject is reduced by at least30%, preferably by at least 40% from baseline after 1 or 2 weekstreatment. In an aspect of the invention, the total nasal symptoms score(TNSS) and the total ocular symptom score (TOSS) can be observed asinstantaneous or reflective or both.

In the context of present invention, evaluation of total nasal symptomsscores (TNSS) include the sum of scores of nasal congestion, rhinorrhea,itching and sneezing from baseline to the end of treatment (e.g., 1 or 2weeks). Further evaluation of the total ocular symptoms scores (TOSS)includes ocular itching, tearing/watery eyes and ocular redness frombaseline to the end of treatment.

In one embodiment, the subject suffers from persistent allergic rhinitisand is treated for 4 or 6 weeks.

In another embodiment, the subject exhibits a positive skin prick testto an allergen. Alternately, the subject may also exhibit positive bloodtests showing an allergy.

In yet another embodiment, the method involves no significanttreatment-related adverse effects in the subject after 1 or 2 weekstreatment.

In another embodiment the present invention relates to a method oftreating seasonal allergic rhinitis and/or nasal symptoms associatedwith seasonal allergic rhinitis in a subject (e.g., a human) in needthereof comprising nasally administering to the subject a synergisticcombination comprising mometasone furoate and olopatadine hydrochloride,wherein the combination is in the form of a pharmaceutical compositioncomprising mometasone furoate and olopatadine hydrochloride in a weightratio of about 1:5 to about 1:60 or from about 1:13.3 to about 1:53.2(based on the equivalent weight of olopatadine free base).

In one embodiment, the present invention related to a method of treatingallergic rhinitis in a human in need thereof comprising nasallyadministering to the human an effective amount of a fixed-dosepharmaceutical composition comprising mometasone or its salt andolopatadine or its salt, wherein (i) the composition is nasallyadministered as 1 or 2 sprays per nostril of the human at least oncedaily, and (ii) each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60 orfrom about 1:13.3 to about 1:53.2 (based on the equivalent weight ofolopatadine free base). The method may provide reduction of at least onetreatment-related adverse effect (e.g. epistaxis and somnolence)relative to the use of the mometasone or olopatadine alone. For example,the method may provide effective treatment of seasonal allergic rhinitisand/or nasal symptoms associated with seasonal allergic rhinitis in asubject with a reduced incidence of drowsiness and nose bleeds. Inanother embodiment, the method may provide effective treatment ofseasonal allergic rhinitis and/or nasal symptoms associated withseasonal allergic rhinitis in a subject without significant drowsinessand/or inducing nose bleeds.

In another embodiment, the present invention relates to a method oftreating perennial allergic rhinitis and/or nasal symptoms associatedwith perennial allergic rhinitis in a subject (e.g., a human) in needthereof comprising nasally administering to the subject a combination(e.g., a synergistic combination) comprising mometasone furoate andolopatadine hydrochloride, wherein the combination is in the form of apharmaceutical composition comprising mometasone furoate and olopatadinehydrochloride in a weight ratio of about 1:5 to about 1:60 or from about1:13.3 to about 1:53.2 (based on the equivalent weight of olopatadinefree base).

In one aspect of this embodiment, each spray comprises about 25 mcg orabout 50 mcg mometasone furoate and olopatadine hydrochloride equivalentto about 600 mcg olopatadine. In one aspect of this embodiment, thepharmaceutical composition is a suspension comprising mometasone or itssalt in particulate form and olopatadine or its salt in solution. In oneaspect of this embodiment, the composition is administered for a periodof at least 1 week as—(i) 1 spray per nostril once daily or twice daily,or (ii) 2 sprays per nostril once daily or twice daily. In yet anotheraspect of this embodiment, the allergic rhinitis is selected fromperennial allergic rhinitis, persistent allergic rhinitis, seasonalallergic rhinitis, and nasal and/or non-nasal symptoms associatedtherewith. In a preferred aspect, the allergic rhinitis is seasonalallergic rhinitis and/or nasal symptoms associated therewith. In yetanother aspect of this embodiment, (i) the total nasal symptoms score(TNSS) of the human is reduced by at least 50% from baseline after 2weeks treatment, and/or (ii) total ocular symptom score (TOSS) of thehuman is reduced by at least 40% from baseline after 2 weeks treatment,and/or (iii) no significant treatment-related adverse effects areobserved in the human after 2 weeks treatment. In one aspect of the saidembodiment, the human exhibits a positive skin prick test to anallergen. In one aspect of the said embodiment, the treatment-relatedadverse effects include somnolence or epistaxis or a combinationthereof.

Another embodiment is a method of treating allergic rhinitis in asubject, wherein the subject exhibits a positive skin prick test to anallergen. The skin prick test can be performed by pricking the skin witha needle or pin containing a small amount of ragweed allergen. In oneembodiment, prior to administration of a combination of olopatadine andmometasone as described herein, the skin prick test was performed on thesubject and resulted in a wheal diameter of at least 3 mm greater than anegative control such as saline.

The methods of treatment described herein can be administered to asubject without the subject exhibiting any significant treatment-relatedadverse effects, for example, after 1 or 2 weeks treatment.

The treatment related adverse effects in the context of the presentinvention may include, but are not limited to, eye disorders (e.g.,conjunctivitis), gastrointestinal disorders (e.g., abdominal distension,diarrhoea, dyspepsia, dysphagia and gastric ulcer, haemorrhoidalhaemorrhage, hyperchlorhydria, nausea and vomiting, and toothache),general disorders (e.g., fatigue, local swelling, peripheral oedema,pain and pyrexia), infections and infestations (e.g., oral herpes andupper respiratory tract infection), injury, poisoning and proceduralcomplications, musculoskeletal and connective tissue disorders (e.g.,arthralgia), nervous system disorders (e.g., disturbance in attention,dizziness, dysgeusia, somnolence and headache), reproductive system andbreast disorder (e.g., dysmenorrhea) respiratory, thoracic andmediastinal disorders (e.g., epistaxis, dry throat, dyspnea, epistaxis,nasal congestion, nasal discomfort, respiratory tract haemorrhage,rhinorrhea, throat irritation, and upper-airway cough syndrome), skinand subcutaneous tissue disorders (e.g., rash and urticaria).

In another embodiment, the present invention relates to a method oftreating seasonal allergic rhinitis and/or nasal symptoms associatedwith seasonal allergic rhinitis in a subject (e.g., a human) in needthereof comprising nasally administering to the subject a synergisticcombination comprising mometasone furoate and olopatadine hydrochloride,wherein the combination is in the form of a pharmaceutical compositioncomprising mometasone furoate and olopatadine hydrochloride in a weightratio of about 1:5 to about 1:60 or from about 1:13.3 to about 1:53.2(based on the equivalent weight of olopatadine free base).

Synergistic effects for the combination of mometasone furoate andolopatadine hydrochloride can be evaluated by various methods. Onemethod for evaluating the efficacy of an agent for treating allergicrhinitis is the ovalbumin induced rhinitis model in guinea pigs. In suchmodels, the effect of the treatment is studied in animals sensitized andchallenged with ovalbumin, followed by detailed analysis of theirsneezing response using whole body plethysmography and the total numberof eosinophils in a nasal lavage sample.

The fixed-dose pharmaceutical composition comprising mometasone or itssalt and olopatadine or its salt may be administered to the subjectaccording to one of the following regimens:

a) the composition is nasally administered as 1 spray per nostril oncedaily for a period of at least 1 week;

b) the composition is nasally administered as 2 sprays per nostril oncedaily for a period of at least 1 week;

c) the composition is nasally administered as 1 spray per nostril twicedaily for a period of at least 1 week;

d) the composition is nasally administered as 2 sprays per nostril twicedaily for a period of at least 1 week;

e) the composition is nasally administered as 1 spray per nostril oncedaily for a period of 2 weeks;

f) the composition is nasally administered as 2 sprays per nostril oncedaily for a period of 2 weeks;

g) the composition is nasally administered as 1 spray per nostril twicedaily for a period of 2 weeks; or

h) the composition is nasally administered as 2 sprays per nostril twicedaily for a period of 2 weeks.

In another embodiment, the present invention relates to a method oftreating seasonal allergic rhinitis and/or nasal symptoms associatedwith seasonal allergic rhinitis in a human in need thereof comprisingnasally administering to the human a synergistic combination comprisingmometasone furoate and olopatadine hydrochloride, wherein thecombination is in the form of a pharmaceutical composition comprisingmometasone furoate in particulate form and olopatadine hydrochloride insolution in a weight ratio of about 1:13.3 to about 1:53.2 (based on theequivalent weight of olopatadine free base), and wherein the compositionis administered as 1 or 2 sprays per nostril of the human, at least oncedaily for a period of at least 1 week wherein the method providesreduction of at least one adverse event. In one aspect of thisembodiment, the composition is administered once daily or twice dailyfor a period of 2 weeks. In another aspect of this embodiment, eachspray comprises about 25 mcg or about 50 mcg of mometasone furoate andabout 665 mcg of olopatadine hydrochloride. In yet another aspect ofthis embodiment, (i) the total nasal symptoms score (TNSS) of the humanis reduced by at least 50% from baseline after 2 weeks treatment, and/or(ii) total ocular symptom score (TOSS) of the human is reduced by atleast 40% from baseline after 2 weeks treatment, and/or (iii) nosignificant treatment-related adverse effects are observed in the humanafter 2 weeks treatment. In one aspect of the said embodiment, the humanexhibits a positive skin prick test to an allergen. Preferably, thetreatment-related adverse effects include somnolence or epistaxis or acombination thereof.

In an aspect of the invention, the fixed-dose pharmaceutical compositionmay be administered for a period of about 1 week, 2 weeks, 4 weeks, 6weeks or 8 weeks. Preferably, the fixed-dose pharmaceutical composition,is administered as 1 or 2 sprays per nostril of the subject (e.g., ahuman), once daily or twice daily for a period of 1 week or 2 weeks. Inanother aspect of the embodiment, each spray of the compositioncomprises olopatadine hydrochloride equivalent to about 600 mcg ofolopatadine and about 25 mcg to about 50 mcg of mometasone furoate.Preferably, each spray of the composition comprises about 665 mcg ofolopatadine hydrochloride (equivalent to about 600 mcg of olopatadine)and about 25 mcg or about 50 mcg of mometasone furoate. In yet anotheraspect, the composition does not have unpleasant odor and taste. In yetanother aspect of the embodiment, the total nasal symptoms score (TNSS)of the human subject is reduced by at least 40% or at least 50% frombaseline after 1 or 2 weeks treatment. In yet another aspect of theembodiment, the total ocular symptom score (TOSS) of the human isreduced by at least 30% or at least 40% from baseline after 1 or 2 weekstreatment. In yet another aspect of the embodiment, the said methodprovides reduction in treatment-related adverse effects. Preferably, thetreatment-related adverse effects include somnolence or epistaxis or acombination thereof. In yet another aspect of the embodiment, the humansubject is a patient exhibiting a positive skin prick test to anallergen.

In one aspect the present invention relates to the use of mometasone orits salt and olopatadine or its salt in a weight ratio of about 1:5 toabout 1:60 or from about 1:12 to about 1:53 for the manufacture of afixed-dose pharmaceutical composition of the invention for the treatmentof allergic rhinitis in a subject (e.g., a human) in need thereof. In anaspect, the fixed-dose pharmaceutical composition is a suspensionwherein mometasone or its salt is present in particle form (e.g., havinga mean particle size of from about 1 to about 20 μm, or from about 1 toabout 15 μm) and olopatadine or its salt is present in dissolved form.In yet another aspect, the composition does not have unpleasant odor andtaste.

In a separate embodiment the present invention relates to a method ofreducing symptoms associated with rhinitis in a subject (e.g. a human)in need thereof, the method comprising nasally administering to thesubject an effective amount of a fixed dose pharmaceutical compositioncomprising mometasone or its salt and olopatadine or its salt in aweight ratio of about 1:5 to about 1:60 or from about 1:12 to about 1:53for about 1 or 2 weeks.

In yet another embodiment, the present invention relates to a method ofreducing symptoms associated with allergic rhinitis in a human in needthereof comprising nasally administering to the human an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasoneor its salt and olopatadine or its salt, wherein (i) the composition isnasally administered as 1 or 2 sprays per nostril of the human at leastonce daily, and (ii) each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60 orfrom about 1:12 to about 1:53 for about 1 or 2 weeks. (based on theequivalent weight of olopatadine free base) and wherein the compositionis administered as 1 or 2 sprays per nostril of the human, at least oncedaily for a period of at least 1 week, wherein the method providesreduction of at least one adverse event. In one aspect of thisembodiment, each spray comprises about 25 mcg or about 50 mcg mometasonefuroate and olopatadine hydrochloride equivalent to about 600 mcgolopatadine. In one aspect of this embodiment, the pharmaceuticalcomposition is a suspension comprising mometasone or its salt inparticulate form and olopatadine or its salt in solution. In one aspectof this embodiment, the composition is administered for a period of atleast 1 week as—(i) 1 spray per nostril once daily or twice daily, or(ii) 2 sprays per nostril once daily or twice daily. In yet anotheraspect of this embodiment, the allergic rhinitis is selected fromperennial allergic rhinitis, persistent allergic rhinitis, seasonalallergic rhinitis, and nasal and/or non-nasal symptoms associatedtherewith. In a preferred aspect, the allergic rhinitis is seasonalallergic rhinitis and/or nasal symptoms associated therewith. In yetanother aspect of this embodiment, (i) the total nasal symptoms score(TNSS) of the human is reduced by at least 50% from baseline after 2weeks treatment, and/or (ii) total ocular symptom score (TOSS) of thehuman is reduced by at least 40% from baseline after 2 weeks treatment,and/or (iii) no significant treatment-related adverse effects areobserved in the human after 2 weeks treatment. In one aspect of the saidembodiment, the human exhibits a positive skin prick test to anallergen. In one aspect of the said embodiment, the symptoms includerhinorrhea, nasal congestion, nasal itching, sneezing, itching/burningeyes, tearing/watering eyes, redness of eyes, itching of ears or palate,coughing, ocular pruritus, excess lacrimation, headache, fatigue andmalaise. In yet another aspect of the embodiment, the treatment-relatedadverse effects include somnolence or epistaxis or a combinationthereof.

The administration of the pharmaceutical composition may provide relieffrom one or more symptoms of allergic rhinitis (such as nasal symptomsor ocular symptoms) in a subject faster (e.g., an onset of action inless than 30 minutes, such as within about 15 minutes, such as within 10minutes) than nasal administration of the mometasone or its salt or theolopatadine or its salt alone. In another embodiment, the administrationmay provide relief from one or more symptoms of allergic rhinitis (suchas nasal symptoms) in a subject exposed to an environmental exposurechamber (EEC) (such as one with ragweed pollen at a concentration of3500±500 particles/m³ for 6 hours) faster (e.g., an onset of action inless than 15 minutes, such as within about 10 minutes) than nasaladministration of the mometasone or its salt or the olopatadine or itssalt alone.

Yet another embodiment is a method for providing faster onset of reliefof symptoms associated with allergic rhinitis in a human subject in needthereof comprising nasally administering twice daily, two sprays pernostril of a fixed-dose pharmaceutical composition comprising mometasoneor its salt (e.g., mometasone furoate) and olopatadine its salt (e.g.,olopatadine hydrochloride). This method may provide faster onset ofrelief of one or more symptoms compared to administration of themometasone or its salt alone or olopatadine or its salt alone. Eachspray may comprise mometasone or its salt and olopatadine or its salt ina weight ratio of about 1:5 to about 1:60 (such as a weight ratio ofabout 1:12 to about 1:53, about 1:13.3 to about 1:50, or from about 1:18to about 1:40) (based on the equivalent weight of olopatadine free base)(for example, each spray comprises about 12.5 mcg, about 25 mcg, about37.5 mcg, about 50 mcg, or about 62.5 mcg of mometasone or its salt(such as about 50 mcg mometasone furoate) and olopatadine hydrochlorideequivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750mcg, or about 900 mcg of olopatadine (such as about 665 mcg olopatadinehydrochloride)). The administration may provide relief from one or moresymptoms within 30 minutes, such as within 15 minutes or within 10minutes. In another embodiment, the administration may provide relieffrom one or more symptoms of allergic rhinitis (such as nasal symptoms)in a subject exposed to an environmental exposure chamber (EEC) (such asone with ragweed pollen at a concentration of 3500±500 particles/m³ for6 hours) in less than 15 minutes, such as within about 10 minutes.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis comprising the step of administering to thesubject a pharmaceutical composition for twice daily nasaladministration of two sprays per nostril, wherein (i) the pharmaceuticalcomposition provides an onset of action within 15 minutes for thetreatment of allergic rhinitis and (ii) each spray of the pharmaceuticalcomposition comprises about 25 mcg of mometasone furoate and about 665mcg of olopatadine hydrochloride.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis comprising the steps of:

(a) prescribing to a subject (e.g., a human subject) a fixed-dosepharmaceutical composition for twice daily nasal administration of twosprays per nostril, wherein the fixed-dose pharmaceutical compositioncomprises mometasone or its salt (such as mometasone furoate) andolopatadine or its salt (such as olopatadine hydrochloride), and eachspray comprises mometasone or its salt and olopatadine or its salt in aweight ratio of about 1:5 to about 1:60 (such as a weight ratio of about1:12 to about 1:53, about 1:13.3 to about 1:50, or from about 1:18 toabout 1:40) (based on the equivalent weight of olopatadine free base)(for example, each spray comprises about 12.5 mcg, about 25 mcg, about37.5 mcg, about 50 mcg, or about 62.5 mcg of mometasone or its salt(such as about 50 mcg mometasone furoate) and olopatadine hydrochlorideequivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750mcg, or about 900 mcg of olopatadine (such as about 665 mcg olopatadinehydrochloride)),

the prescribing being performed in response to (i) marketing of thepharmaceutical composition as (A) providing faster onset of action (suchas an onset of action within less than 30 minutes, such as within 15minutes, such as within 10 minutes) for relief of one or more symptoms(e.g., nasal symptoms) of allergic rhinitis than nasal administration ofmometasone or its salt (such as 25 or 50 mcg mometasone furoate) orolopatadine or its salt (such as 665 mcg olopatadine hydrochloride)alone, (B) providing relief of one or more symptoms of allergic rhinitiswithin 15 minutes (or 30 minutes), and (ii) diagnosis of the humansubject as suffering from allergic rhinitis, or (C) providing fasteronset of action (such as within 15 minutes, such as within about 10minutes) for relief of one or more symptoms (e.g., nasal symptoms) ofallergic rhinitis in subjects exposed to an environmental exposurechamber (EEC) (such as one with ragweed pollen at a concentration of3500±500 particles/m³ for 6 hours) than nasal administration of themometasone or its salt or the olopatadine or its salt alone. (D)providing relief from one or more symptoms of allergic rhinitis (such asnasal symptoms) in subjects exposed to an environmental exposure chamber(EEC) (such as one with ragweed pollen at a concentration of 3500±500particles/m³ for 6 hours) within 15 minutes, such as within about 10minutes; and

(b) administering the prescribed pharmaceutical composition to thesubject. In one preferred embodiment, each spray of the fixed-dosepharmaceutical composition provides 25 mcg mometasone furoate and 665mcg olopatadine hydrochloride.

Yet another embodiment is a method of treating a human subject sufferingfrom allergic rhinitis (such as seasonal allergic rhinitis or perennialallergic rhinitis) comprising the step of administering to the subject aprescribed fixed-dose pharmaceutical composition for twice daily nasaladministration of two sprays per nostril, where the fixed-dosepharmaceutical composition comprises mometasone or its salt (such asmometasone furoate) and olopatadine or its salt (such as olopatadinehydrochloride), and each spray comprises mometasone or its salt andolopatadine or its salt in a weight ratio of about 1:5 to about 1:60(such as a weight ratio of about 1:12 to about 1:53, about 1:13.3 toabout 1:50, or from about 1:18 to about 1:40) (based on the equivalentweight of olopatadine free base) (for example, each spray comprisesabout 12.5 mcg, about 25 mcg, about 37.5 mcg, about 50 mcg, or about62.5 mcg of mometasone or its salt (such as about 50 mcg mometasonefuroate) and olopatadine hydrochloride equivalent to about 300 mcg,about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg ofolopatadine (such as about 665 mcg olopatadine hydrochloride)). Thepharmaceutical composition is prescribed in response to (a) marketing ofthe pharmaceutical composition as (A) providing faster onset of action(such as an onset of action within less than 30 minutes, such as within15 minutes, such as within 10 minutes) for relief of symptoms (e.g.,nasal symptoms) of allergic rhinitis than nasal administration ofmometasone or its salt (such as 50 mcg mometasone furoate) orolopatadine or its salt (such as 665 mcg olopatadine hydrochloride)alone or (B) providing relief of one or more symptoms of allergicrhinitis within 15 minutes (or 30 minutes), and (b) a diagnosis of thesubject as suffering from allergic rhinitis. In one preferredembodiment, each spray of the fixed-dose pharmaceutical compositionprovides 25 mcg mometasone furoate and 665 mcg olopatadinehydrochloride.

Another embodiment relates to a method of reducing eosinophil count inthe nasal lavage of a subject by nasally administering an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasoneor its salt and olopatadine or its salt in a weight ratio of about 1:5to about 1:60 (based on the equivalent weight of olopatadine free base),wherein the method provides a greater reduction in eosinophil count thanthat provided by mometasone or its salt or olopatadine or its salt whenadministered as a monotherapy. The eosinophil count can be measured byany known technique, such as with a hemocytometer.

Yet another embodiment relates to a method of reducing total cell countin the nasal lavage by nasally administering an effective amount of afixed-dose pharmaceutical composition comprising mometasone or its saltand olopatadine or its salt in a weight ratio of about 1:5 to about 1:60(based on the equivalent weight of olopatadine free base) wherein themethod provides a greater reduction in total cell count than thatprovided by mometasone or its salt or olopatadine or its salt whenadministered as a monotherapy.

In the context of the present invention, eosinophil count and total cellcount can be measured using various instruments such as a hemocytometer.Sneezing response can be determined using instruments such as a wholebody plethysmography (Buxco Research Systems, Wilmington, N.C., USA).

In the context of the present invention, the fixed dose pharmaceuticalcomposition comprising mometasone or its salt, olopatadine or its saltare preferably supplied in the form of nasal spray with one or morepharmaceutical acceptable excipients (e.g., chelating agents,preservatives, buffer, surfactants, isotonic agent, taste maskingagents, suspending agents, humectants, antioxidants and diluents) in acontainer and a kit providing directions on its usage andadministration. The pharmaceutical composition may, for example, haveany one of the formulations described in International PatentApplication No. PCT/IB2014/064251, filed Sep. 4, 2014, U.S. patentapplication Ser. No. 14/483,837, filed Sep. 11, 2014, U.S. patentapplication Ser. No. 14/662,128, filed Mar. 18, 2015, U.S. patentapplication Ser. No. 15/183,534, filed Jun. 15, 2016, and U.S. patentapplication Ser. No. 15/210,692, filed Jul. 14, 2016, each of which ishereby incorporated by reference in its entirety.

The pharmaceutical composition can be nasally administered with a nasalspray device (e.g., one capable of delivery a mist spray in the nostrilsof a subject for local action on nasal mucosa).

Pharmaceutical Compositions

The pharmaceutical composition can contain an effective amount ofmometasone or a salt thereof and olopatadine or a salt thereof. Theeffective amount of mometasone or its salt can range from about 0.01 mgto about 10 mg or preferably from about 0.02 mg to about 5 mg. Theeffective amount of olopatadine or its salt in the pharmaceuticalcomposition can range from about 0.05 mg to about 20 mg, or preferablyfrom about 0.1 mg to about 15 mg.

For daily administration by the nasal route, the effective amount ofmometasone or its salt in the pharmaceutical composition can range fromabout 10 mcg to about 500 mcg, or preferably from about 20 mcg to about400 mcg, and that for olopatadine or its salt can ranges from about 50mcg to about 7000 mcg, or preferably from about 100 mcg to about 5400mcg.

The term “average particle size” (or synonymously, “mean particle size”)as used herein refers to the distribution of particles, wherein about 50volume percent of all the particles measured have a size less than thedefined average particle size value and about 50 volume percent of allparticles measured have a particle size greater than the defined averageparticle size value. This can be identified by the term “D₅₀” or“d_((0.5))”. The average particle size can be measured using varioustechniques such as microscopy, laser diffraction, photon correlationspectroscopy (PCS) and Coulter's principle.

The term “C_(max)” is the maximum concentration of a drug (e.g.,mometasone or olopatadine) in the blood plasma.

The term “T_(max)” is the time at which the peak (maximum) blood plasmadrug concentration is achieved.

The term “AUC_(0-∞)” is the mean area under the plasmaconcentration-time curve extrapolated to infinity. It is calculated asthe arithmetic mean of the area under the plasma concentration-timecurve from time 0 extrapolated to infinity.

The term AUC_(tau)” is the area under the curve for a plasma, serum orblood concentration versus time curve of a drug reached by a given doseover one dosing interval at steady state. The area under the curve ismeasured for a time tau at steady state, where tau is the length of thedosing interval.

The term “hydrocolloid” refers to a colloid system wherein hydrophiliccolloid particles (e.g., hydrophilic polymers) are dispersed in water.The hydrocolloid system can exist in gel state or sol (liquid) state. Insuspension compositions, the hydrocolloids function as thickening,stabilizing and suspending agents. Non-limiting examples ofhydrocolloids include xanthan gum, gum arabic, guar gum, locust beangum, alginate, starch, agar-agar, carrageenan, gelatin, a mixture ofmicrocrystalline cellulose (MCC) and sodium carboxymethyl cellulose(sodium CMC) (e.g., Avicel RC591® (available from FMC Biopolymer,Philadelphia, Pa.), a mixture of MCC and sodium CMC with a sodium CMCcontent of 8.3-13.8%), and cellulose derivatives (e.g., carboxymethylcellulose sodium). Preferably, the hydrocolloid includes xanthan gum orcarboxymethylcellulose sodium.

Some embodiments of the present invention provide compositionscomprising carboxymethylcellulose sodium. In some embodiments, thecompositions comprise from about 0.08 to about 2% carboxymethylcellulosesodium. In some embodiments, the compositions comprise from about 0.1%w/w to about 1.5% w/w carboxymethylcellulose sodium. In someembodiments, the compositions comprise from about 0.12% w/w to about 1%w/w carboxymethylcellulose sodium. In some embodiments, the compositionscomprise from about 0.15% w/w to about 0.75% w/w carboxymethylcellulosesodium. In some embodiments, the compositions comprise about 0.083% w/wcarboxymethylcellulose sodium. In some embodiments, the compositionscomprise 0.0830% w/w carboxymethylcellulose sodium. In some embodiments,the compositions comprise about 0.1% w/w carboxymethylcellulose sodium.In some embodiments, the compositions comprise 0.0996% w/wcarboxymethylcellulose sodium. In some embodiments, the compositionscomprise about 0.7% w/w carboxymethylcellulose sodium. In someembodiments, the compositions comprise 0.6656% w/wcarboxymethylcellulose sodium.

The term “container” refers to single unit-dose container or multi-dosecontainer. Suitable single unit-dose containers or multi-dose containersinclude, but are not limited to, glass, aluminum, polypropylene or highdensity polyethylene, for example, high density polyethylene containersproduced using a blow-fill-seal manufacturing technique. In oneembodiment, the container is a sprayer which delivers the pharmaceuticalcomposition in the form of a fine mist. A sprayer generally includes acontainer containing a pharmaceutical composition, a pump sealed (e.g.,hermetically engaged) with the container, an actuator removablyreceiving a top portion of the pump, and a cap removably engaged withthe container and the actuator.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administration toa human, where the composition comprises about 0.001% w/w to about0.075% w/w mometasone or its salt and about 0.5% w/w to about 0.8% w/wolopatadine or its salt.

The pharmaceutical composition may be in the form of a solution or asuspension, but preferably the composition is in the form of asuspension (more preferably, a single phase suspension), whereinmometasone or its salt is present in particle form and olopatadine orits salt is present in dissolved form. The mometasone or its salt andolopatadine or its salt may be present at a weight ratio of about 1:3 toabout 1:106, or from about 1:5 to about 1:53 or preferably from about1:5 to about 1:36. In one embodiment, the weight ratio of mometasone orits salt and olopatadine or its salt in the composition is from about1:10 to about 1:53 or from about 1:12 to about 1:30.

The composition preferably also includes a hydrocolloid. In oneembodiment, the composition is a suspension and includes a hydrocolloidin a sufficient amount to prevent phase separation (i.e., separation ofthe particles and solution) after 3 or 6 months of storage at 25±2° C.and 60%±5% relative humidity (RH) or at 40±2° C. and 75%±5% RH. In oneembodiment, the aqueous pharmaceutical composition is a single phasesuspension which remains a single phase suspension even after 3 or 6months of storage at 25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5%RH.

Another embodiment is an aqueous pharmaceutical composition comprising(a) mometasone or its salt, (b) olopatadine or its salt, and (c) afibrillar network comprising a cellulosic material. The fibrillarnetwork may have interfibrillar spaces. In one embodiment, theinterfibrillar spaces contain one or more mometasone particles. In someembodiments, the mometasone or its salt is present in particulate formhaving an average particle size of less than about 15 μm. In furtherembodiments, the mometasone particles are equidistantly, orsubstantially equidistantly, spaced within the fibrillar network. Theaverage distance between adjacent mometasone particles may be spacedsufficiently to provide consistent delivery of a fixed amount (or aneffective amount) of both the mometasone (or its salt) and olopatadine(or its salt), for example, for 30, 56, 60, 120, or 240 doses (e.g., bynasal spray administration). In some embodiments, the fibrillar networkis at least partially responsible for the ability of the compositions ofthe present invention to provide consistent dosing of a fixed amount, oran effective amount, of the active ingredients to the target site. Theolopatadine or its salt in such compositions may be in dissolved form.

The term ‘stable’ as used in connection with aqueous suspensions refersto a composition when shaken and then stored for at least 24 hours atambient condition does not show phase separation on visual inspection.Preferably, such stable composition does not show phase separation for aperiod of at least 3 days, or at least 5 days, or at least 7 days. Inone aspect, the ‘stable’ composition of the present invention shows,upon shaking (e.g., for 1 minute) and visual inspection, no lumpformation and a total impurity content of no more than 1.0% afterstorage at ambient conditions (at about 25° C. and a relative humidityof about 60%) for a period of at least 6 months.

In the context of the present invention, the drug content and impuritiescan be determined by various analytical techniques such as HPLC, LC-MS,TLC and the like.

It was observed that when various pharmaceutical compositions for nasaladministration comprising mometasone or its salt and olopatadine or itssalt were prepared, the compositions generally showed physicalseparation in the suspension composition. This physical instabilityfurther leads to lack of dose uniformity. Surprisingly, it was foundthat addition of a hydrocolloid at certain concentrations (e.g. at aconcentration of at least about 0.1% w/w) in the suspension compositionyielded a physically stable composition (with no separation) suitablefor nasal administration.

Another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises about 0.025%w/w to about 0.05% w/w mometasone or its salt, about 0.6% w/w to about0.7% w/w olopatadine or its salt and a hydrocolloid which includescarboxymethylcellulose sodium and xanthan gum. The hydrocolloid may bepresent at a concentration of at least about 0.1% w/w of thecomposition.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid which comprises xanthan gum. Thexanthan gum may be present at a concentration of at least about 0.1%w/w, or preferably between about 0.3% w/w to about 3% w/w of thecomposition.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalsuspension composition (e.g., contained in a container) for nasaladministration to a human, comprising about 0.025% w/w to about 0.05%w/w mometasone furoate, about 0.6% w/w to about 0.7% w/w olopatadinehydrochloride and a hydrocolloid which comprises sodium carboxymethylcellulose. The sodium carboxymethyl cellulose may be present at aconcentration of at least about 0.1% w/w, or preferably between about0.1% w/w to about 3% w/w of the composition.

Yet another embodiment is a stable fixed dose aqueous pharmaceuticalcomposition in the form of suspension (e.g., contained in a container)for nasal administration to a human, comprising mometasone or itspharmaceutically acceptable salt, olopatadine or its pharmaceuticallyacceptable salt, a hydrocolloid (e.g., at a concentration of at leastabout 0.1% w/w of the composition) and a pharmaceutical acceptableexcipient.

It will also be appreciated to the skilled artisan that in order toimprove the physical properties, appearances, or smells of thecomposition of the present invention, one or more furtherpharmaceutically acceptable excipients may be added as desired. Suitablepharmaceutical acceptable excipients include, but are not limited to,chelating agents, preservatives, buffers, surfactants, isotonicityagents, taste masking agents, antioxidants, humectants, pH adjustingagents, and any combination of any of the foregoing.

Suitable surfactants which can be used for preparing aqueous nasal spraycomposition may include one or more of anionic, cationic, non-ionic orzwitterionic surfactants.

Examples of suitable surfactants which can be employed in the aqueousnasal spray suspension may be selected from, but not limited to,polyethoxylated sorbitan derivatives such as polysorbates, their etherethoxylates, produced by reaction of sorbitan esters with ethyleneoxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether,polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate,polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate,polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylenesorbitol lanolin derivative, polyoxyethylene tridecylether,polyoxyethylene sorbitan esters of mixed fatty and resin acids,polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitanmonooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether,polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether,polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine,polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitanmonopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylenestearate, polyoxyethylene lauryl ether, polyoxyethylene lanolinderivative, sodium oleate, quaternary ammonium derivative, potassiumoleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfateor mixtures thereof. Preferred surfactants are polyethoxylated sorbitanderivatives (such as polysorbate 80). The amount of surfactant may rangefrom about 0.001% to about 1% w/w relative to the total weight of thecomposition.

In order to improve the ability of the aqueous nasal spray suspension tobe tolerated on administration to the nasal mucous membrane, it isadvantageous to formulate it as isotonic. The osmolality can be set byvariation of the amounts of the substances present in the aqueous nasalspray suspension besides mometasone, olopatadine and any furthersubstances present, and/or by addition of an isotonicity agent,preferably a physiologically tolerated salt, such as, for example,sodium chloride or potassium chloride, or a physiologically toleratedpolyol, such as, for example, a sugar alcohol, in particular sorbitol orglycerol, in the concentration necessary for rendering isotonic.

Examples of suitable preservatives which can be employed in the aqueousnasal spray suspension include, but are not limited to, benzyl alcohol,quaternary ammonium halides, phenylcarbinol, thimerosal, and disodiumedetate. Quaternary ammonium halide preservatives are preferred.Suitable quaternary ammonium halide preservatives includepolyquaternium-1 and benzalkonium halides. Preferred benzalkoniumhalides include benzalkonium chloride and benzalkonium bromide. Theamount of the preservative present in the aqueous nasal spray suspensionmay range from about 0.005 to about 0.2% w/w relative to the totalweight of the composition. Preferably, the preservative is present at aconcentration of about 0.02% w/w relative to the total weight of thecomposition.

Examples of suitable chelating agents which can be employed in theaqueous nasal spray suspension include, but are not limited to, edetatedisodium (EDTA), edetate trisodium, edetate tetrasodium, anddiethyleneamine pentaacetate, preferably EDTA. The amount of thechelating agent present in the aqueous nasal spray suspension of thepresent invention may range from about 0.0002 to about 0.5% w/w relativeto the total weight of the composition.

Examples of suitable buffers which can be employed in the aqueous nasalspray suspension include, but are not limited to, citric acid, aceticacid, fumaric acid, hydrochloric acid, malic acid, nitric acid,phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphatesalts (e.g., dibasic sodium phosphate, such as dibasic sodium phosphateheptahydrate), or combinations thereof. The suspension of the presentinvention may comprise an amount of a buffer sufficient to maintain thepH of the composition to from about 3 to about 6. Preferably, the amountof buffer ranges from about 0.005% to about 1% w/w relative to the totalweight of the composition.

Examples of suitable sweetener/taste masking agents which can beemployed in the aqueous nasal spray suspension include, but are notlimited to, sucralose, thaumatin (e.g., Talin®), sucrose, saccharin(including salt forms such as sodium and calcium salts), fructose,glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol,sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol,eucalyptus oil, camphor, and natural or artificial flavors or flavoringagents (for example menthol, mints, vanilla, orange, etc.), orcombinations of two or more of such agents. A particularly preferredtaste masking agent is sucralose. The amount of the sweetener/tastemasking agent present in the aqueous nasal spray suspension may rangefrom about 0.01% to about 1% w/w relative to the total weight of thecomposition.

Examples of suitable antioxidants which can be employed in the aqueousnasal spray suspension include, but are not limited to, ascorbic acid,alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylatedhydroxytoluene, glutathione, and any combination of any of theforegoing. The amount of the antioxidants present in the aqueous nasalspray composition may range from about 0.0002% to about 0.5% w/wrelative to the total weight of the composition.

Examples of suitable humectants which can be employed in the aqueousnasal spray suspension include, but are not limited to, glycerin,sorbitol, polyethylene glycol, propylene glycol or mixtures thereof,which are mixed with a suitable humectant vehicle such as water. Theamount of humectant present in the aqueous nasal spray suspension mayrange from about 0.0002% to about 0.5% w/w relative to the total weightof the composition.

Suitable pH adjusting agents include, but are not limited to, sodiumhydroxide and hydrochloric acid.

In the context of present invention, the pharmaceutical stable fixeddose suspension composition for nasal administration may have a pH ofbetween about 3.3 and about 4.1, or between about 3.5 and about 3.9. Theinventors discovered that the olopatadine hydrochloride crystallizes outof the fixed dose combination aqueous suspension at a pH of 5 to 5.5.The olopatadine hydrochloride, however, remains dissolved in the aqueoussuspension at a pH of about 3.3 to about 4.1.

The aqueous pharmaceutical composition preferably is substantially freeof crystals of olopatadine hydrochloride. In one embodiment, the aqueouspharmaceutical composition contains less than 2%, less than 1%, lessthan 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition. In another embodiment, the aqueouspharmaceutical composition is substantially free of crystals ofolopatadine hydrochloride after 3 or 6 months of storage at 25±2° C. and60%±5% RH or at 40±2° C. and 75%±5% RH. In yet another embodiment, theaqueous pharmaceutical composition contains less than 2%, less than 1%,less than 0.5%, less than 0.2%, or less than 0.1% of crystallineolopatadine hydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 3 or 6 months of storage at25±2° C. and 60%±5% RH or at 40±2° C. and 75%±5% RH.

The osmolality of the composition may range between about 200 mOsm/kgand about 400 mOsm/kg, or about 250 mOsm/kg and about 350 mOsm/kg. Theviscosity of the composition may be about 10 cps to about 200 cps orpreferably from about 20 cps to about 150 cps.

In yet another aspect, the pharmaceutical composition in the form ofsuspension and contains mometasone furoate in particles having meanparticle size in the range of from about 1 μm to about 20 μm, orpreferably from about 1 μm to about 15 μm. In an aspect, the suspensionpharmaceutical composition of the present invention has mean particlesize of less than 15 μm when determined by microscopy technique.

In yet another aspect, the pharmaceutical composition, upon nasaladministration (e.g., as a nasal spray) of a dose equivalent to 200 mcgof mometasone or its salt to a human, results in (a) an area under thecurve (AUC)_(0-∞) for mometasone or its salt of about 50 pg·hr/mL toabout 140 pg·hr/mL, preferably from about 68 pg·hr/mL to about 124pg·hr/mL, (b) a C_(max) for mometasone or its salt of about 6.5 pg/mL toabout 16 pg/ml, preferably from about 8.6 pg/mL to about 12.9 pg/ml, (c)a T_(max) for mometasone or its salt of about 15 minutes to about 120minutes, or (d) any combination of any of the foregoing.

In yet another aspect, the pharmaceutical composition, upon nasaladministration (e.g., as a nasal spray) of a dose equivalent to 2400 mcgof olopatadine or its salt to a human, results in (a) an AUC_(0-∞) forolopatadine or its salt of about 42.5 ng·hr/mL to about 116.5 ng·hr/mL,preferably from about 56.7 ng·hr/mL to about 99.8 ng·hr/mL, (b) aC_(max) for olopatadine or its salt of about 10.3 ng/mL to about 24.1ng/ml, preferably from about 13.8 ng/mL to about 20.7 ng/ml, (c) aT_(max) of about 15 minutes to about 120 minutes, or (d) any combinationof any of the foregoing.

In yet another aspect, the pharmaceutical composition, upon nasaladministration (e.g., as a nasal spray) of a dose equivalent to 100 mcgof mometasone or its salt (e.g., mometasone furoate) to a human for thefirst time, results in (a) an area under the curve (AUC)_(tau) formometasone or its salt of about 12 pg·hr/mL to about 73 pg·hr/mL,preferably from about 20 pg·hr/mL to about 36 pg·hr/mL, (b) a C_(max)for mometasone or its salt of about 3 pg/mL to about 13 pg/ml,preferably from about 5 pg/mL to about 9 pg/ml, (c) a T_(max) formometasone or its salt of about 15 minutes to about 120 minutes, or (d)any combination of any of the foregoing. In yet another aspect, thepharmaceutical composition, upon nasal administration (e.g., as a nasalspray) of a dose equivalent to 100 mcg of mometasone or its salt (e.g.,mometasone furoate) to a human at steady state (e.g., after 8 days oftwice daily administration of 100 mcg of mometasone or its salt),results in (a) an area under the curve (AUC)_(tau) for mometasone or itssalt of about 26 pg·hr/mL to about 124 pg·hr/mL, preferably from about40 pg·hr/mL to about 80 pg·hr/mL, (b) a C_(max) for mometasone or itssalt of about 4 pg/mL to about 16 pg/ml, preferably from about 8 pg/mLto about 12 pg/ml, (c) a T_(max) for mometasone or its salt of about 15minutes to about 120 minutes, or (d) any combination of any of theforegoing.

In yet another aspect, the pharmaceutical composition, when delivered asa nasal spray has a spray pattern having a longest axis of about 15-75mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

In the context of present invention, the viscosity can be determined byvarious known instruments such as a Dynamic stress rheometer orBrookfield viscometer. In a preferred embodiment, the viscosity isdetermined by a Brookfield viscometer by measuring torque transmissionthrough a sample using a rotating spindle.

In another embodiment, the present invention relates to a stable fixeddose, aqueous pharmaceutical composition (e.g., contained in acontainer) for nasal administration to a human, where the compositioncomprises about 0.001% w/w to about 0.075% w/w mometasone furoatemonohydrate and about 0.5% w/w to about 0.8% w/w olopatadinehydrochloride.

Another embodiment is a stable fixed dose pharmaceutical composition inthe form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises xanthan gumat a concentration of about 0.3% w/w of the composition, wherein thecomposition has a pH between about 3.5 and about 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical compositionin the form of suspension (e.g., contained in a container) for nasaladministration to a human, comprising mometasone furoate monohydrate,olopatadine hydrochloride and a hydrocolloid which comprises sodiumcarboxymethyl cellulose at a concentration of about 0.5% w/w of thecomposition, wherein the composition has a pH between about 3.5 andabout 3.9.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 0.02% w/w benzalkonium chloride, (5) about 0.4% w/w sodiumchloride, (6) about 0.01% w/w di-sodium edetate, (7) about 0.94% w/wsodium phosphate heptahydrate, and (8) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.025% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 1% w/w to about 1.2% w/w mixture of microcrystalline celluloseand carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable fixed dose pharmaceutical aqueoussuspension composition (e.g., contained in a container) for nasaladministration to a human, where the composition comprises (1) about0.050% w/w mometasone furoate monohydrate, (2) about 0.665% w/wolopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3%w/w of xanthan gum and about 0.5% w/w carboxymethyl cellulose sodium,(4) about 1% w/w to about 1.2% w/w mixture of microcrystalline celluloseand carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkoniumchloride, (6) about 0.4% w/w sodium chloride, (7) about 0.01% w/wdi-sodium edetate, (8) about 0.94% w/w sodium phosphate heptahydrate,and (9) about 0.01% w/w polysorbate 80.

Yet another embodiment is a stable suspension suitable for nasaladministration to a human, comprising (a) an aqueous solvent, (b)particles of mometasone furoate suspended in the solvent, the particleshaving a mean particle size of from about 1 to about 20 μm, (c)olopatadine hydrochloride dissolved in the solvent, and (d) ahydrocolloid, the suspension having a viscosity in the range of about 20cps to about 150 cps. In one preferred embodiment, the suspension has apH of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg toabout 350 mOsm/kg. In one embodiment, the suspension further comprises achelating agent, a preservative, a buffer, a surfactant, an isotonicityagent, and optionally a pH adjusting agent.

Preferably, the suspensions of the present invention have only one phase(i.e., they are preferably a single phase suspension).

In a further embodiment, the present invention relates to kit comprisinga stable fixed dose, aqueous pharmaceutical composition of the presentinvention contained in a container for nasal administration and apackage insert containing instructions about the use of saidpharmaceutical composition. In one preferred embodiment, the containeris part of a sprayer which has an actuator. When the actuator isactuated, the composition is delivered in the form of a spray.

In a further embodiment, the pharmaceutical composition is contained ina sprayer, and has, on deliver a spray of the composition to a humannose, a spray pattern having a longest axis of 15-75 mm, a shortest axisof 10-65 mm, and an ellipticity of 1-2.

In the context of present invention, the pharmaceutical composition whendelivered as a nasal spray using a sprayer yields a specific spraypattern and spray droplet size. The spray pattern can be determined byvarious known techniques such as with an ADSA with NSPUA set up (InnovaSystem) and the spray droplet size distribution can be determined byvarious known techniques such as with a Malvern Spraytec with NSPUA setup (Innova System).

The following describes a typical procedure for characterizing dropletsize distribution of the spray—The sprayer is loaded with a compositionas described above and primed by an actuating pump via an actuator untila fine mist appears out of the nozzle of the sprayer. A commerciallyavailable laser diffraction instrument is arranged so that the nozzle isabout 3 cm or 6 cm below the laser beam of the laser diffractioninstrument. The pump is actuated with a conventional mechanical actuatorusing a constant force. The resulting spray of the composition crossesthe laser beam. Data are collected for D₁₀, D₅₀, D₉₀, SPAN, and % Volume<10 μm. The average values for each of these parameters for three spraysare calculated.

One embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 50 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

Yet another embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition comprising mometasone furoate monohydrate, olopatadinehydrochloride and optionally a hydrocolloid contained in a sprayer,wherein each spray of the aqueous pharmaceutical composition provides(i) mometasone furoate monohydrate equivalent to about 25 mcg ofmometasone furoate and (ii) olopatadine hydrochloride equivalent toabout 600 mcg olopatadine.

The stable aqueous nasal spray suspension of mometasone and olopatadinemay comprise one or more additional pharmaceutical active agent/sselected from the therapeutic category of, but not limited to,non-steroidal anti-inflammatory agents, decongestants, and anycombination of any of the foregoing.

The aqueous nasal spray suspension can be administered as a drop or anyother form suitable for topical administration. The composition may alsobe administered using a nasal tampon or a nasal sponge.

In a preferred embodiment, the aqueous suspension is provided in theform of nasal spray wherein the suspension is administered in a singleunit-dose container or multi-dose container. Suitable single unit-dosecontainers or multi-dose containers include, but are not limited to,glass, aluminum, polypropylene or high density polyethylene, forexample, high density polyethylene containers produced using ablow-fill-seal manufacturing technique.

In one embodiment, the pharmaceutical composition is contained within aspray bottle (such as a sprayer). The spray bottle may include acontainer for storing the pharmaceutical composition and a pump forspraying the pharmaceutical composition intranasally. In one embodiment,the container is capable of storing 30, 56, 60, or 120, or 240 doses.For example, a container storing 240 doses can provide a 1 month supplyof the pharmaceutical composition (2 sprays per nostril twice daily (8sprays per day) for 30 days). A container storing 56 doses can provide a1 week supply of the pharmaceutical composition (2 sprays per nostriltwice daily (8 sprays per day) for 7 days). In one embodiment, thecontainer may be suitable for containing 9-10 mL (e.g., 9 mL or 56doses), 18-19 mL of the pharmaceutical composition (e.g., 18 mL or 120doses), or 29-30 mL (e.g., 29 mL or 240 doses) of the pharmaceuticalcomposition.

In certain additional embodiments, the invention provides a multi dosagecomposition of matter, comprising: (a) a multi-unit dosage of apharmaceutical composition of the present invention; and (b) a containercomprising: (i) a squeezable chamber holding the multi dosage of thecomposition and having an opening wherein the dosage exits the openingwhen the squeezable chamber is squeezed; and (ii) a closure mechanismremovably attached to the opening of the squeezable chamber. In certainembodiments, the multi dosage container is made of a moldable polymer.

In such embodiments, suitable polymers include, but are not limited to,polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny),polyvinyl chloride (PVC), polyethylene terephthalate (PET),polycarbonate (PC), polyoxymethylene (POM), polysulfon (PSF),polyethersulfon (PES), polyacrylate (PAR), and polyamid (PA). In certainembodiments, polymers include polyethylene, particularly medium-densitypolyethylene (MDPE) (or branched polyethylene) or high densitypolyethylene (HDPE) (or linear, polyethylene). In one embodiment, themulti dose container is made of high density polyethylene (HDPE).

Other means for delivering the nasal spray, such as inhalation via ametered dose inhaler (MDI), may also be used. Several types of MDIs areregularly used for administration by inhalation. These types of devicescan include breath-actuated MDIs, spacer/holding chambers in combinationwith MDIs, and nebulizers. The term “MDI” as used herein refers to aninhalation delivery system comprising, for example, a canistercontaining a mixture of an active agent and a propellant optionally withone or more excipients, a metered dose valve, an actuator, and amouthpiece. The canister is usually filled with a suspension of anactive agent, such as the nasal spray composition, and a propellant,such as one or more hydrofluoroalkanes [e.g. 1, 1, 1,2-tetrafluoroethane (HFA-134a) and 1, 1, 1, 2, 3, 3,3-heptafluoropropane (HFA-227)], chlorofluorocarbons, and alcohols suchas ethanol, isopropanol, butanol, propanol or mixtures thereof. When theactuator is depressed a metered dose of the suspension is aerosolizedfor inhalation. Particles comprising the active agent are propelledtowards the mouthpiece where they may then be inhaled by a subject.

A further embodiment is a stable fixed dose, aqueous pharmaceuticalcomposition (e.g., contained in a container) for nasal administrationcomprising about 0.025% w/w to about 0.05% w/w mometasone or its saltand about 0.5 w/w to about 0.8% w/w olopatadine or its salt for thetreatment of rhinitis in a human in need thereof.

The following examples are provided to enable one skilled in the art topractice the invention and these are merely illustrative of theinvention and should not be read as limiting the scope of the invention.

EXAMPLES Example 1 Effect of Mometasone and Olopatadine and theirCombination on Ovalbumin Induced Rhinitis Model in Male Guinea Pigs

Male Dunkin Hartley guinea pigs were actively sensitized with asubcutaneous injection of 1.5 mg of ovalbumin and 20 mg of aluminumhydroxide gel on days 0 and 7. Guinea pigs were sensitized intranasallywith 2% ovalbumin from days 14-17. On day 28, the animals werechallenged with 6% ovalbumin intranasally.

Animal Grouping

Actively sensitized animals were randomly assigned to one of thefollowing 5 groups during the experiment (see Table 1).

A: Saline Control (vehicle treated/saline challenged),

B: Ovalbumin Control (vehicle treated/ovalbumin challenged),

C: Olopatadine hydrochloride 50 μg (based on the equivalent weight ofolopatadine free base) (olopatadine hydrochloride 50 μgtreated/ovalbumin challenged),

D: Mometasone furoate 10 μg (mometasone furoate 10 μg treated/ovalbuminchallenged) and

E: Combination (mometasone furoate 10 μg+olopatadine hydrochloride 50 μg(based on the equivalent weight of olopatadine free base)treated/ovalbumin challenged).

Compound Administration

Mometasone furoate 10 μg was given intranasally 24 hours and 1 hourprior to the final ovalbumin challenge. Olopatadine hydrochloride wasgiven intranasally 1 hour before the final ovalbumin challenge. Thedosing volume was 40 μl/animal. The saline control group and ovalbumincontrol group received vehicle (40 μl, 0.1% Tween 80 in distilledwater).

TABLE 1 Animal Groups Ovalbumin Animals/ Group Group Code TreatmentChallenge group A Saline Vehicle − 6 Control B Ovalbumin Vehicle + 7Control C Olopatadine Olopatadine + 7 50 μg Hydrochloride 50 μg DMometasone Mometasone + 6 10 μg Furoate 10 μg E CombinationOlopatadine + 7 Hydrochloride 50 μg + Mometasone Furoate 10 μg

In Vivo Evaluation Measurement of Sneezing Response

Sneezing response was determined by using whole body plethysmography(Buxco Research Systems, USA) for 50 minutes after final saline orovalbumin challenge.

Nasal Lavage

Nasal lavage was performed at 4 hours after challenge of animals withsaline or ovalbumin on day 28. Animals were anesthetized with anoverdose of urethane, the trachea was exposed and nasal lavage wasperformed using 2 mL pre-warmed normal saline. The collected nasallavage was taken for total cell count using a hemocytometer. The nasallavage was centrifuged, and the cell pellet resuspended in 15 μL guineapig serum and used for preparation of smears. Slides were stained withLeishman's stain and a differential cell count of 100 cells based onstandard morphology was performed manually.

Calculations

The total number of eosinophils in each nasal lavage sample wascalculated using the formula:

${{Total}{{No}.{of}}{eosinophils}( {{in}{nasal}{lavage}} )} = \frac{{Total}{cell}{count} \times 10^{5}/{mL} \times {Percent}{eosinophils}}{100}$

Percent inhibition of eosinophils was calculated using the followingformula:

${\%{Inhibition}{of}{eosinophils}} = {\frac{{{Avg}.{eosinophils}_{({{Ovalbumin}{control}})}} - {eosinophils}_{({compound})}}{{{Avg}.{eosinophils}_{({{Ovalbumin}{control}})}} - {{Avg}.{eosinophils}_{({{Saline}{Control}})}}} \times 100}$

Data Analysis

Data was statistically analyzed using one way ANOVA followed byDunnett's multiple comparison tests.

Results

Mometasone furoate monotherapy showed significant inhibition of totalcell and eosinophils in nasal lavage but was not effective in inhibitingsneezing response. Olopatadine hydrochloride monotherapy did not showsignificant inhibition of any of the parameters in this model. Thecombination of mometasone furoate with olopatadine hydrochloride showedsynergy for inhibition of sneezing response (FIG. 1 ), cellularinfiltration in nasal lavage (FIG. 2 ) and nasal eosinophilia (FIG. 3 )as compared to respective monotherapy arms (see Table 2).

TABLE 2 Summary of the effects of a combination of mometasone furoateand olopatadine hydrochloride on ovalbumin induced rhinitis model inguinea pigs. Olopatadine Mometasone Saline Ovalbumin HydrochlorideFuroate Combination Treatment control control (OH) (MF) (OH & MF)) Dose— — 50 10 50 (OH) & 10 (MF) (μg per animal) Number of Sneeze 0.5** 22    12.29 18.83  6* (0-50 min) Percent inhibition — — 45 15 74 ofsneeze Total cell count × 0.48*** 6.79 6.63 3.90*     2.46*** 10⁵/mlnasal lavage Percent inhibition of — — 3 46 69 total cell countEosinophils × 10⁵/ 0.03*** 3.71 3.64 2.00*     1.26** ml nasal lavage %inhibition of — — 2 46 67 eosinophils *P < 0.05 vs. Ovalbumin Control,**P < 0.01 vs. Ovalbumin Control, ***P < 0.001 vs. Ovalbumin control

The combination of mometasone furoate and olopatadine hydrochlorideshowed a beneficial effect greater than the individual monotherapies.The combination of mometasone furoate and olopatadine hydrochlorideshowed synergy in the treatment of allergic rhinitis in this model.

Example 2 Effect of Mometasone and Olopatadine and their Combination onOvalbumin Induced Rhinitis Model in Male Guinea Pigs

The procedure in Example 1 was repeated except 120 μg of olopatadinehydrochloride (based on the equivalent weight of olopatadine free base)was used. The animal groups in Table 3 below were used during thisexperiment.

TABLE 3 Animal Groups Ovalbumin Animals/ Group Group Code TreatmentChallenge group A Saline Vehicle − 9 Control B Ovalbumin Vehicle + 10Control C Olopatadine Olopatadine + 10 120 μg Hydrochloride 120 μg DMometasone Mometasone Furoate + 9 10 μg 10 μg E CombinationOlopatadine + 10 Hydrochloride 120 μg + Mometasone Furoate 10 μg

Compound administration was performed as in Example 1, except the dosingvolume was 60 μl/animal. The saline control group and ovalbumin controlgroup received vehicle (60 μl, 0.1% Tween 80 in distilled water). Invivo evaluations were performed as in Example 1.

Results

Mometasone monotherapy showed significant inhibition of total cell andeosinophils in nasal lavage but was not effective in inhibiting sneezingresponse. Olopatadine monotherapy did not show significant inhibition ofany of the parameter in this model. The combination of mometasone witholopatadine showed synergy for the inhibition of nasal eosinophilia,cellular infiltration in nasal lavage and sneezing response as comparedto the respective monotherapies (see FIGS. 4-6 and Table 4).

TABLE 4 Summary of the effects of combination of mometasone andolopatadine on ovalbumin induced rhinitis model in guinea pigsOlopatadine Mometasone Saline Ovalbumin Hydrochloride FuroateCombination Treatment control control (OH) (MF) (OH & MF) Dose — — 12010 120 (OH) & (μg per animal) 10 (MF) Number of Sneeze 0.89*** 35.70 17.90 37.33 13.30* (0-50 min) Percent inhibition — — 51 −5 64 of sneezeTotal cell count × 0.58*** 6.88 5.83 4.96 3.66*** 10⁵/ml nasal lavagePercent inhibition of — — 17 30 51 total cell count Eosinophils ×0.03*** 3.36 3.08 2.69 1.66** 10⁵/ml nasal lavage % inhibition of — — 820 51 eosinophils *P < 0.05 vs. Ovalbumin Control, **P < 0.01 vs.Ovalbumin Control, ***P < 0.001 vs. Ovalbumin Control

The combination of mometasone furoate and olopatadine hydrochlorideshowed a beneficial effect greater than the individual monotherapies.The combination of mometasone and olopatadine showed synergy in thisguinea pig rhinitis model.

Example 3 Clinical Study of Fixed Dose Combination of Mometasone andOlopatadine Nasal Spray in Human Patients

The study was a single-centre, double blind, double-dummy, randomized,parallel-group, comparative Environmental Exposure Chamber (EEC) studyto evaluate the efficacy, safety and tolerability of (i) two fixed dosecombination products of mometasone furoate and olopatadine hydrochloridenasal spray, (ii) a fixed dose combination of azelastine hydrochlorideand fluticasone propionate nasal spray (DYMISTA®), (iii) olopatadinenasal spray (PATANASE®), and (iv) a placebo nasal spray in patients withseasonal allergic rhinitis (SAR).

Key Objectives

-   -   To evaluate the efficacy of two strengths of the fixed dose        combination (FDC) of mometasone furoate and olopatadine        hydrochloride nasal spray when compared with a placebo nasal        spray.    -   To evaluate the comparative efficacy of (i) two regimens of FDC        products containing mometasone furoate and olopatadine        hydrochloride nasal spray, (ii) a fixed dose combination of        azelastine hydrochloride and fluticasone propionate nasal spray        (DYMISTA®), and (iii) Olopatadine nasal spray (PATANASE®).    -   To compare the efficacy of (i) a fixed dose combination of        azelastine hydrochloride and fluticasone propionate nasal spray        and (ii) olopatadine nasal spray, when compared with a placebo        nasal spray.    -   To compare the onset of action between active treatments groups        after the first dose defined as “the first time point after        initiation of treatment when the drug demonstrates a significant        reduction in instantaneous TNSS compared to the placebo        treatment that proves durable from this point.”    -   To compare the EEC-Quality of Life Questionnaire (QoLQ) and        tolerability and acceptability between a fixed dose combination        of mometasone furoate and olopatadine hydrochloride once daily        and a fixed dose combination of mometasone furoate and        olopatadine hydrochloride twice daily.    -   To evaluate the comparative safety between the various treatment        arms.

Sample Size

A total of 36 patients per treatment arm were randomized in the study.The total number of randomized subjects throughout the five treatmentarms was 180.

Patient Population

Subjects suffering from seasonal allergic rhinitis for the last twoyears that require treatment either with intranasal antihistaminesand/or intranasal steroids were included in the study.

Key Subject Selection Criteria

1. Patients age ≥18 and ≤65 years inclusive of either sex;

2. Patient with a known clinical history of seasonal allergic rhinitis(for at least 2 years) and exhibiting a positive skin prick test (whealdiameter at least 3 mm greater than saline control) to one of theregional allergens;

3. Patients with the ability to understand and sign a written informedconsent form, which must have been obtained prior to screening; and

4. Patients willing to comply with the protocol requirements.

Study Design

Patients were randomized to treatment in a 1:1:1:1:1 ratio to thefollowing five treatment arms, at one study site:

1. Fixed dose combination of olopatadine hydrochloride 665 mcg andmometasone furoate 25 mcg twice daily (BID)

2. Fixed dose combination of olopatadine hydrochloride 665 mcg andmometasone furoate 50 mcg once daily (QD)

3. DYMISTA® nasal spray (azelastine hydrochloride 137 mcg+fluticasonepropionate 50 mcg) Spray twice daily (BID)

4. PATANASE® nasal spray (olopatadine hydrochloride 665 mcg) twice daily(BID)

5. Placebo nasal spray

The double-dummy design including four masked nasal spray bottles (twofor evening dosing and two for morning dosing) were utilized for thisstudy (see Table A).

TABLE A Treatment Administration Using Four Masked Bottles of NasalSprays Morning Evening 1^(st) 2^(nd) 1^(st) 2^(nd) Treatment Arm bottlebottle bottle bottle 1 TP-1: Fixed dose combination Active Active ActiveActive of mometasone furoate 25 mcg + olopatadine hydrochloride 665 mcgtwice daily (BID) 2 TP-2: Fixed dose combination Active Active PlaceboPlacebo of mometasone furoate 50 mcg + olopatadine hydrochloride 665 mcgonce daily (QD) 3 DYMISTA ® twice Placebo Active Placebo Active daily(BID) 4 PATANASE ® twice Active Active Active Active daily (BID) 5Placebo Placebo Placebo Placebo Placebo

This study consisted of five visits to the study site and a 12 dayat-home dosing period (and 2 days of onsite dosing—a total of 14 days ofdosing). Assessment of efficacy endpoints were done out of season, in anEEC facility. After the initial screening visit (Visit 1), patients whomet all study criteria (including the main criteria for inclusion: apositive skin prick test (SPT) and a 2 year medical history of allergicrhinitis (AR) to ragweed allergen) underwent further screening/primingin the EEC (Visit 2). During the EEC session patients were exposed toragweed pollen at a concentration of 3500±500 particles/m³ for 6 hours.Patients used an electronic diary (ePDAT™) to rate their ocular andnasal symptoms every 30 minutes in the EEC Patients who met a minimumqualifying TNSS of 6/12, including a score of at least 2 for nasalcongestion on two consecutive diary entries continued in the study. AtVisit 3, on the following day (Day 1), patients who met the minimumcriteria returned to the EEC for a second consecutive EEC session.Patients were exposed to allergen for approximately 10 hours during thisvisit. During the first 6 hours, patients used the electronic diary tocomplete symptom assessments every 30 minutes and met the minimumqualifying symptom score in order to continue. Those who met the minimumqualifying symptom score were randomized to receive one of the fivestudy drugs after the 6 hours time point in the EEC. After dosing (atapproximately noon), patients were asked to complete symptom assessmentsat 5 minute, 10 minutes, 15 minutes, 25 minutes, 30 minute, 45 minutes,60 minutes and then every 30 minutes for the remainder of the visitPost-treatment symptom assessments in the EEC were used to determineonset of action for study treatments. Patients were then sent home withtheir study medication to continue at-home BID dosing starting from theevening dose for Day 1. Patients continued at-home dosing for a periodof 12 days. Following the 12 days (Days 2-13) of at-home dosing,patients returned to the EEC on Day 14 (Visit 4) for a post-treatment6-hour priming EEC session. Patients were dosed with the morning dose ofstudy drug one hour prior to entering the EEC. Symptoms were assessedevery 30 minutes in the EEC Patients took their last dose of studytreatment at midnight on the same day, and returned on the followingmorning (Day 15, Visit 5) for a 6 hour EEC session Over a period of 6hours, patients used the electronic diary to complete symptomassessments every 30 minutes. In addition to collection of nasal andocular symptoms, the electronic diary was used to collectEEC-Quality-of-Life Questionnaires (EEC-QoLQ) at Visits 2, 3, 4 and 5,and acceptability and tolerability at Visit 5. Visit 5 was the finalvisit for the study.

Priming

Fulfillment of the following criteria on each of two consecutive diarycards reading at priming visit: minimum TNSS of 6 out of 12, including ascore of at least 2 for nasal congestion.

Randomization

-   -   Patients meeting these same criteria at both priming visits of 3        hours chamber duration in order to proceed to the treatment        visit (Visit 3).    -   At the treatment visit (Visit 3), a minimum TNSS of 6 out of 12        (including a score of at least 2 for nasal congestion).

Drug Formulations

The test product formulations used in the study were as follows:

Test Product 1 (TP-1)

Mometasone Furoate Monohydrate and Olopatadine Hydrochloride Nasal Spray(25 mcg+600 mcg)

Each spray delivered mometasone furoate monohydrate equivalent to 25 mcgmometasone furoate and olopatadine hydrochloride equivalent to 600 mcgolopatadine.

Test Product 2 (TP-2)

Mometasone Furoate Monohydrate and Olopatadine Hydrochloride Nasal Spray(50 mcg+600 mcg)

Each spray delivered mometasone furoate monohydrate equivalent to 50 mcgmometasone furoate and olopatadine hydrochloride equivalent to 600 mcgolopatadine.

Dosage Regimen 1. Investigational Products

-   -   TP-1: Fixed dose combination of Olopatadine hydrochloride (665        mcg) and Mometasone furoate (25 mcg) Nasal Spray: 2 sprays per        nostril were delivered Twice daily (BID) for two weeks.    -   TP-2: Fixed dose combination of Olopatadine hydrochloride (665        mcg) and Mometasone furoate (50 mcg) Nasal Spray: 2 sprays per        nostril were delivered once daily (QD) for two weeks

2. Reference Therapies

-   -   Olopatadine hydrochloride Nasal Spray (PATANASE® 0.6%): 2 sprays        per nostril were delivered twice daily for two weeks.    -   DYMISTA® (azelastine hydrochloride+fluticasone propionate) 137        mcg/50 mcg Nasal Spray: 1 spray per nostril was delivered twice        daily for two weeks.    -   Placebo Nasal Spray (based on vehicle of Investigational        product): 2 sprays per nostril were delivered twice daily for        two weeks.

Key Evaluation Criteria (Clinical Endpoints)

-   -   Change from baseline in mean post-treatment Total Nasal Symptoms        Score (TNSS) over placebo for fixed dose combination of        mometasone furoate and olopatadine hydrochloride. Mean TNSS were        calculated over 6 hours in the EEC for post-treatment at Visit 5        (over hours 18 to 24 after the first dosing on Day 14) and        matched baseline TNSS in the EEC at Visit 3 (over 6 hours prior        to first dosing).    -   Change from baseline in mean post-treatment TNSS for two        regimens of fixed dose combination of mometasone furoate and        olopatadine hydrochloride with reference products: DYMISTA®        nasal spray and PATANASE® nasal spray. Mean TNSS were calculated        over 6 hours in the EEC for post-treatment at Visit 5 (over        hours 18 to 24 after the first dosing on Day 14) and matched        baseline TNSS in the EEC at Visit 3 (over 6 hours prior to first        dosing).    -   Change from baseline in mean post-treatment TNSS for two        regimens of fixed dose combination of mometasone furoate and        olopatadine hydrochloride, DYMISTA® nasal spray and PATANASE®        nasal spray. Mean post-treatment TNSS were calculated over 6        hours in the EEC for post-treatment at Visit 4 (over hours 1 to        7 after first dosing on Day 14) and matched baseline TNSS in the        EEC at Visit 2 (over 6 hours).    -   Change from baseline in mean post-treatment TNSS for two        regimens of fixed dose combination of mometasone furoate and        olopatadine hydrochloride compared with reference products:        DYMISTA® nasal spray and PATANASE® nasal spray. Mean TNSS were        calculated over 12 hours in the EEC for post-treatment (at Visit        4 over 1 to 7 hours after first dosing on Day 14, and at Visit 5        over 18 to 24 hours after first dosing on Day 14) and matched        baseline TNSS in the EEC at Visit 2 and Visit 3 (over 12 hours        prior to first dosing).    -   Onset of Action for each treatment of fixed dose combination of        mometasone furoate and olopatadine hydrochloride, DYMISTA® and        PATANASE® were assessed by comparing change from baseline in        post-treatment TNSS between each active treatment and placebo at        every time point after the first treatment. Change from baseline        in TNSS were calculated at every time point after the first dose        of study treatment in the EEC at Visit 3 (i.e., over the last        four hours in the EEC at Visit 3) with baseline (Visit 3)        defined as the average of the last two time points pre-dosing.    -   Change from baseline in mean post-treatment Total Symptoms Score        (TSS), Individual Nasal Symptoms Scores (NSS, four nasal        symptoms of rhinorrhea, pruritus, sneezing and nasal congestion)        and TOSS over 6 hours in the EEC at Visit 5 and matched baseline        at Visit 3 (over 6 hours prior to first dosing).    -   Change from baseline in mean post-treatment Total Symptoms Score        (TSS), Individual Nasal Symptoms Scores (NSS, four nasal        symptoms of rhinorrhea, pruritus, sneezing and nasal congestion)        and TOSS over the 6 hours in the EEC at Visit 4 and matched        baseline at Visit 2 (over the 6 hours in the EEC).    -   Change from baseline in mean post-treatment Total Symptoms Score        (TSS), Individual Nasal Symptoms Scores (NSS, four nasal        symptoms of rhinorrhea, pruritus, sneezing and nasal congestion)        and TOSS over 12 hours in the EEC at Visit 4 and Visit 5 and        matched baseline over 12 hours in the EEC prior to dosing at        Visit 2 and Visit 3.    -   EEC-QoLQ for all treatment arms by comparing 1) pre-EEC-QoLQ at        baseline (Visit 2) with pre-EEC at Visit 4; 2) post-EEC at        baseline Visit 2 with post-EEC at Visit 4; 3) after 6 hours in        the EEC at Visit 3 (prior to first dosing) with post-EEC at        Visit 5.    -   Reflective tolerability and acceptability for treatment arms        compared to placebo post-EEC at Visit 5.

Results

Table B shows a summary of the TNSS change from baseline topost-treatment over 6 hours in EEC (ITT Population).

TABLE B DYMISTA ® ® PATANASE Parameters Placebo TP-1 TP-2 (Reference)(Reference) N 36 36 36 36 36 Baseline EEC Mean 7.64 8.07 8.20 8.67 8.27EEC at the end Mean 6.61 3.31 3.94 4.80 6.38 of treatment (2 weeks) %Change from — 13.35 58.98 51.95 45.67 22.85 Baseline

Table C shows a summary of the TNSS change from baseline topost-treatment over 12 hours in EEC (ITT Population). (The data forNASONEX in Table C is sourced from its U.S. FDA approved label.)

TABLE C PATANASE ® DYMISTA ® Parameters TP-1 TP-2 (Reference) NASONEX ®*(Reference) N 36 36 36 176 36 Baseline EEC Mean 7.58 7.85 7.90 9.60 8.25EEC at the end Mean 2.85 3.36 5.72 — 4.34 of treatment (2 weeks) %Change from — 62.4 57.07 27.5 27.92 48.24 Baseline *NASONEX ®(mometasone furoate nasal spray) US FDA Approved label (Jan. 19, 2011)

Table D shows a summary of the TOSS change from baseline topost-treatment over 12 hours in EEC (ITT Population).

TABLE D PATANASE ® DYMISTA ® Parameters TP-1 TP-2 (Reference)(Reference) N 36 36 36 36 Baseline EEC Mean 3.97 4.17 3.92 4.54 EEC atthe end of Mean 1.97 2.34 2.82 2.82 treatment (2 weeks) % Change from —50.37 43.6 28.3 37.88 Baseline

The results of the study show that a combination of mometasone furoateand olopatadine hydrochloride, when administered nasally to a humanpatient, provides an effective treatment of seasonal allergic rhinitisand clinically significant reduction in both nasal and non-nasalsymptoms associated therewith. The magnitude of this relief for TNSS wasclinically relevant (i.e., greater than 2 units in difference—which isgenerally considered as clinically relevant—between the Test Productsand Placebo). Test Product-1 showed overall better symptom relief ascompared to the Reference Products (PATANASE® and DYMISTA®). Onset ofaction occurred by 10 minutes for TP-1 based on iTNSS change frombaseline after the first dose at Visit 3 (−1.26). However, onset ofaction could not be defined for TP-2, DYMISTA, and PATANASE asstatistically significant differences in iTNSS change from baselinebetween these treatments and placebo treatment were not observed at any2 consecutive time points.

Example 4 Phase II Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Human Patients

The study is a double-blind, randomized, parallel-group, comparativestudy to evaluate the efficacy, safety and tolerability of two differentstrengths and regimens of a fixed dose combination of mometasone furoateand olopatadine hydrochloride nasal spray compared with a placebo nasalspray and individual monotherapy formulations of olopatadinehydrochloride nasal spray and mometasone furoate nasal spray, insubjects (12 years of age and older) with seasonal allergic rhinitis(SAR).

Key Objectives

-   -   To compare the efficacy of mometasone furoate and olopatadine        hydrochloride nasal spray once daily and mometasone furoate and        olopatadine hydrochloride nasal spray twice daily with the        placebo nasal spray and with the individual constituent        monotherapies at the same dose in the same vehicle over 14 days        of study treatment.    -   To compare the onset of action between mometasone furoate and        olopatadine hydrochloride nasal spray once daily and mometasone        furoate and olopatadine hydrochloride nasal spray twice daily        with the placebo and the individual constituent monotherapies at        the same dose in the same vehicle, after the first dose of study        drug administration.    -   To assess the safety and tolerability of individual treatment        arms.

TABLE E Investigational products and their administration CodeInvestigational product(s) Administration TP-1 Olopatadinehydrochloride + Twice daily (BID) in mometasone furoate (665 μg +morning and evening 25 μg) nasal sprays TP-2 Olopatadine hydrochloride +Once daily (QD) in mometasone furoate (665 μg + morning 50 μg) nasalspray GO-1 Olopatadine hydrochloride Once daily (QD) in (665 μg) nasalspray morning GO-2 Olopatadine hydrochloride Twice daily (BID) in (665μg) nasal spray morning and evening GM-1 Mometasone furoate Once daily(QD) in (50 μg) nasal spray morning GM-2 Mometasone furoate Twice daily(BID) in (25 μg) nasal spray morning and evening

Sample Size:

A total of 1,106 randomized subjects (158 subjects per treatment arm)were enrolled in the study.

Key Subject Selection Criteria:

-   -   Age ≥12 and older inclusive of either sex.    -   Documented clinical history of SAR (for at least 2 years        preceding the screening visit) with exacerbations (clinical        evidence of active symptoms) and exhibiting a documented        positive SPT (wheal diameter at least 5 mm greater than control        wheal) to mountain cedar allergen.    -   A 12-hour reflective TNSS ≥8 out of a possible 12 and a        congestion score of ≥2 for the AM assessment at the Screening        Visit (Visit 1).

Study Design:

Subjects were randomized to treatment in a 1:1:1:1:1:1:1 ratio to thefollowing seven treatment arms, at multiple study sites.The double-dummy design including two identical nasal spray bottles (onefor morning [AM] dosing and one for evening [PM] dosing) are utilizedfor this study (Table F). The double-dummy design is ensured foradequate blinding considering that treatments being compared vary indosing frequency (BID compared with QD).

TABLE F Treatment Administration Using Two Identical Bottles of NasalSprays (2 sprays per nostril, total 4 sprays each bottle, per day)Morning Evening (AM) (PM) Code Treatment Arm 1^(st) bottle 2^(nd) bottleTP-1 Olopatadine hydrochloride 665 μg + Active Active mometasone furoate25 μg twice daily (BID) TP-2 Olopatadine hydrochloride 665 μg + ActivePlacebo mometasone furoate 50 μg once daily (QD) GO-1 Olopatadinehydrochloride nasal Active Placebo spray (665 μg) once daily (QD) GO-2Olopatadine hydrochloride nasal Active Active spray (665 μg) twice daily(BID) GM-1 Mometasone furoate nasal spray (50 Active Placebo μg) oncedaily (QD) GM-2 Mometasone furoate nasal spray (25 Active Active μg)twice daily (BID) Pbo Placebo nasal spray Placebo PlaceboThis study consisted of four visits to the study site. After the initialscreening visit (Visit 1), subjects who met all study selection criteriawere required to undergo a single-blind placebo run-in period for 7-10days. Following the completion of the run-in period, eligible subjectsmeeting the randomization criteria were enrolled and randomized to oneof the seven treatment arms. Subjects were dispensed medication as perthe randomization list. Randomized subjects were required to undergo a 2week (14 days) treatment period as per the protocol to assess theefficacy and safety of the assigned treatment.

Key Evaluation Criteria (Clinical Endpoints): Primary Endpoint

-   -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS (reflective TNSS) over the 14-day treatment        period.

Secondary Endpoints

-   -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS (instantaneous TNSS) over the 14 day treatment        period.    -   Change from baseline in average AM and PM subject-reported        12-hour rTOSS (reflective TOSS) over the 14-day treatment        period.    -   Onset of action for each treatment are assessed by comparing the        change from baseline in post-treatment iTNSS between each active        treatment and placebo at defined time points (prior to first        dose (pre-dose), 15 min, 30 min, 45 min, 60 min, 90 min, 120        min, 150 min, 180 min, 210 min, and 240 min) after the first        study treatment for 4 hours.    -   Change from baseline in the rhinoconjunctivitis quality of life        questionnaire (RQLQ) on day 15 between treatment arms for        subjects with impaired quality of life at baseline as defined by        the RQLQ Score at the randomization visit (RV) of 3.0 or greater        (RQLQ population).

Tertiary Efficacy Endpoints Nasal Symptoms:

-   -   Change from baseline in AM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        nasal symptoms over the 14-day treatment period (AM, PM and        average of AM and PM).    -   Change from baseline in subject-reported instantaneous        individual nasal symptoms over the 14-day treatment period (AM,        PM and average of AM and PM).    -   Change from baseline in average AM and PM subject-reported rTNSS        and iTNSS for each day.    -   Change from baseline in AM subject-reported rTNSS and iTNSS for        each day.    -   Change from baseline in PM subject-reported rTNSS and iTNSS for        each day.

Ocular Symptoms:

-   -   Change from baseline in average AM and PM subject-reported iTOSS        (instantaneous TOSS) over the 14-day treatment period.    -   Change from baseline in AM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        ocular symptoms over the 14-day treatment period (AM, PM and        average AM and PM).    -   Change from baseline in subject-reported instantaneous        individual ocular symptoms over the 14-day treatment period (AM,        PM and average AM and PM).    -   Change from baseline in average of the AM and PM        subject-reported rTOSS and iTOSS for each day.    -   Change from baseline in AM subject-reported rTOSS and iTOSS for        each day.    -   Change from baseline in PM subject-reported rTOSS and iTOSS for        each day.        The non-nasal symptoms are assessed in a similar manner to the        ocular symptoms above.

Physician Assessed Nasal Symptom Score (PNSS) and RhinoconjuntivitisQuality of Life Questionnaire (RQLQ):

-   -   Physician assessed Nasal Symptom Score (PNSS) and physician        assessed individual nasal symptoms at Day 15 (Visit 4).    -   Individual domains of the RQLQ at Day 15 (Visit 4) for the RQLQ        population (defined as subject with impaired Quality of Life at        baseline).    -   RQLQ at Day 15 (Visit 4) for the full analysis set (FAS).

Results

Table G shows a summary of the primary clinical endpoint (rTNSS) andsecondary clinical endpoints (iTNSS, rTOSS, onset of action and RQLQ)observed during this Phase II study. For comparison of the combinationtherapy against a monotherapy, a p-value below 0.05 is consideredstatistically significant.

TABLE G Primary Clinical Treatment Endpoint Secondary Clinical endpointsArm rTNSS iTNSS rTOSS Onset of Action RQLQ TP-2 vs −1.10* p < 0.001*−1.10 p < 0.001* −0.55 p = 0.004* 150 min. −0.48 p = 0.004* PboStatistically significant at all time points after 150 min (except 180min)* TP-2 vs −0.77 p = 0.002* −0.86 p = 0.0003* −0.36 p = 0.65 NA −0.29p = 0.085 GO-1 TP-2 vs −0.35 p = 0.15 −0.34 p = 0.145 −0.37 p = 057 NA−0.13 p = 0.429 GM-1 TP-1 vs −1.17* p < 0.001* −1.10 p < 0.001* −0.41 p= 0.032 Not statistically −0.56 p = 0.0009* Pbo significant at all timepoints TP-1 vs −0.49 p = 0.048* −0.45 p = 0.058 −0.03 p = 0.849 NA −0.25p = 0.135 GO-2 TP-1 vs −0.71 p = 0.004* −0.65 p = 0.006* −0.40 p = 040*NA −0.41 p = 0.014* GM-2 *indicates statistical significance

As can be seen from Table G, the combination of mometasone fuorate andolopatadine hydrochloride, when administered once daily (TP-2) or twicedaily (TP-1) is statistically superior to placebo (p<0.0001) for theprimary endpoint, change in rTNSS from baseline. The combination ofmometasone fuorate and olopatadine hydrochloride, when administered oncedaily (TP-2) or twice daily (TP-1) also met secondary clinical endpointsin the trial, supportive of its efficacy in the treatment of seasonalallergic rhinitis (SAR). The combination of mometasone fuorate andolopatadine hydrochloride, when administered twice daily (TP-1) was alsostatistically superior to the individual monotherapies (GO-2 and GM-2)for both primary (rTNSS) and secondary endpoints (iTNSS).

Table G2 shows the least squares mean difference in individualreflective nasal symptoms scores for TP-1 and TP-2 versus placebo.

TABLE G2 Least Squares Mean Difference in Individual Reflective NasalSymptom Scores with TP-1 or TP-2 versus Placebo Least squares meandifference (97.5% confidence interval) P value TP-1 Rhinorrhea −0.27(−0.42, −0.12) <0.001 Nasal congestion −0.24 (−0.38, −0.99) <0.001 Nasalitching −0.27 (−0.43, −0.11) <0.001 Sneezing −0.39 (−0.57, −0.22) <0.001TP-2 Rhinorrhea −0.26 (−0.40, −0.11) <0.001 Nasal congestion −0.22(−0.37, −0.08) <0.001 Nasal itching −0.26 (−0.42, −0.10) <0.001 Sneezing−0.37 (−0.55, −0.20) <0.001

Table H shows a summary of the treatment emergent adverse events (TEAEs)observed during this Phase II study.

TABLE H Pbo TP-2 GM-1 GO-1 TP-1 GM-2 GO-2 (N = 159) (N = 158) (N = 160)(N = 158) (N = 157) (N = 159) (N = 160) At least 1 13  15  15  17  17 10  25  TEAE (8.2%) (9.5%) (9.4%) (10.8%)  (10.8%)  (6.3%) (15.6%) Dysgeusia 0 2 0 2 2 0 5 (1.3%) (1.3%) (1.3%) (3.1%) Headache 1 6 2 1 0 11 (0.6%) (3.8%) (1.3%) (0.6%) (0.6%) (0.6%)

All TEAEs were mild to moderate. Dysgeusia (1.3%) and headache (1.9%)were adverse events (AEs) reported for the combination of mometasonefuorate and olopatadine hydrochloride administered twice daily (BID) andonce daily (QD), respectively.

Example 5 Phase III Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Human Patients with SAR,Spring Season

This study was a double-blind, randomized, parallel-group, comparativestudy to evaluate the efficacy, safety and tolerability of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray compared with a placebo nasal spray and individual monotherapyformulations of olopatadine hydrochloride nasal spray and mometasonefuroate nasal spray, in subjects (12 years of age and older) withseasonal allergic rhinitis (SAR), spring season.

Study Objectives

-   -   To compare the efficacy of mometasone furoate and olopatadine        hydrochloride nasal spray twice daily with the placebo nasal        spray and with the individual constituent monotherapies at the        same dose in the same vehicle over 14 days of study treatment.    -   To assess the safety and tolerability of individual treatment        arms.    -   To investigate the pharmacokinetics (PK) of mometasone furoate        and olopatadine hydrochloride nasal spray twice daily treatment.

TABLE I Investigational products and their administration CodeInvestigational product(s) Administration TP-1 Olopatadinehydrochloride + Twice daily (BID) in mometasone furoate (665 μg +morning and evening 25 μg) nasal spray GO-2 Olopatadine hydrochlorideTwice daily (BID) in (665 μg) nasal spray morning and evening GM-2Mometasone furoate (25 Twice daily (BID) in μg) nasal spray morning andevening

Sample Size:

A total of 1,180 randomized subjects (295 subjects per treatment arm)were enrolled in the study.

Key Subject Selection Criteria:

-   -   Age ≥12 and older inclusive of either sex.    -   Documented clinical history of SAR (for at least 2 years        preceding the screening visit) with exacerbations (clinical        evidence of active symptoms) during the study season for        mountain season pollen and exhibiting a documented positive SPT        (wheal diameter at least 5 mm greater than control wheal) to        mountain cedar allergen.    -   A 12-hour reflective TNSS ≥8 out of a possible 12 and a        congestion score of ≥2 for the AM assessment at the Screening        Visit (Visit 1).

Study Design:

Subjects were randomized to treatment in a 1:1:1:1 ratio to thefollowing four treatment arms, at multiple study sites.

TABLE J Treatment Administration Using Two Identical Bottles of NasalSprays (2 sprays per nostril, total 4 sprays each bottle, per day)Morning Evening (AM) (PM) Code Treatment Arm 1^(st) bottle 2^(nd) bottleTP-1 Olopatadine hydrochloride 665 μg + Active Active mometasone furoate25 μg twice daily (BID) GO-2 Olopatadine hydrochloride nasal ActiveActive spray (665 μg) twice daily (BID) GM-2 Mometasone furoate nasalspray (25 Active Active μg) twice daily (BID) Pbo Placebo nasal sprayPlacebo Placebo

This study consisted of four visits to the study site. After the initialscreening visit (Visit 1), subjects who met all study selection criteriawere required to undergo a single-blind placebo run-in period for 7-10days. Following the completion of the run-in period, eligible subjectsmeeting the randomization criteria were enrolled and randomized to oneof the four treatment arms. Subjects were dispensed medication as perthe randomization list. Randomized subjects were required to undergo a 2week (14 days) treatment period as per the protocol to assess theefficacy and safety of the assigned treatment. Subjects were instructedto record the symptom scores in a symptom assessment diary. They werealso scheduled to have at least two blood samples for PK assessmentduring the treatment period.

Key Evaluation Criteria (Clinical Endpoints): Primary Endpoint

-   -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS (reflective TNSS) over the 14-day treatment        period.

Secondary Endpoints

-   -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS (instantaneous TNSS) over the 14 day treatment        period.    -   Change from baseline in average AM and PM subject-reported        12-hour rTOSS (reflective TOSS) over the 14-day treatment        period.    -   Onset of action for each treatment are assessed by comparing the        change from baseline in post-treatment iTNSS between each active        treatment and placebo at defined time points (prior to first        dose (pre-dose), 15 min, 30 min, 45 min, 60 min, 90 min, 120        min, 150 min, 180 min, 210 min, and 240 min) after the first        study treatment for 4 hours.    -   Change from baseline in the overall Rhinoconjunctivitis Quality        of Life questionnaire (RQLQ)-Standardized Activities (RQLQ(S))        score on Day 15 (Visit 4) for the Full Analysis Set (FAS).

Pharmacokinetic Endpoints

-   -   Plasma PK: Maximum plasma concentration (C_(max)), time to        attain C_(max) (T_(max)), and area under the plasma        concentration-time curve over the dosing interval (AUC_(tau))        will be estimated for mometasone furoate and olopatadine on Day        1 and Day 8 based on the pharmacokinetic analysis set (PKAS).

Tertiary Efficacy Endpoints Nasal Symptoms:

-   -   Change from baseline in AM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        nasal symptoms over the 14-day treatment period (AM, PM and        average of AM and PM).    -   Change from baseline in subject-reported instantaneous        individual nasal symptoms over the 14-day treatment period (AM,        PM and average of AM and PM).    -   Change from baseline in average AM and PM subject-reported rTNSS        and iTNSS for each day.    -   Change from baseline in AM subject-reported rTNSS and iTNSS for        each day.    -   Change from baseline in PM subject-reported rTNSS and iTNSS for        each day.

Ocular Symptoms:

-   -   Change from baseline in average AM and PM subject-reported iTOSS        (instantaneous TOSS) over the 14-day treatment period.    -   Change from baseline in AM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        ocular symptoms over the 14-day treatment period (AM, PM and        average AM and PM).    -   Change from baseline in subject-reported instantaneous        individual ocular symptoms over the 14-day treatment period (AM,        PM and average AM and PM).    -   Change from baseline in average of the AM and PM        subject-reported rTOSS and iTOSS for each day.    -   Change from baseline in AM subject-reported rTOSS and iTOSS for        each day.    -   Change from baseline in PM subject-reported rTOSS and iTOSS for        each day.        The non-nasal symptoms are assessed in a similar manner to the        ocular symptoms above.

Physician Assessed Nasal Symptom Score (PNSS), RhinoconjuntivitisQuality of Life Questionnaire Standardized Activities (RQLQ(S)), andRhinitis Control Assessment Test (RCAT):

-   -   Change from baseline in PNSS and physician assessed individual        nasal symptoms at Day 15 (Visit 4).    -   Change from baseline in individual domains of the RQLQ(S) at Day        15 (Visit 4) for the FAS.    -   Change from baseline in overall RQLQ(S) score and individual        domains of the RQLQ(S) at Day 15 (Visit 4) for the RQLQ(S)        analysis set.    -   Change from baseline in the RCAT at Day 15 (Visit 4).    -   Change from baseline in individual domains of the RCAT at Day 15        (Visit 4).    -   Individual domains of the RQLQ at Day 15 (Visit 4) for the RQLQ        population (defined as subject with impaired Quality of Life at        baseline).    -   RQLQ at Day 15 (Visit 4) for the full analysis set (FAS).

Results

Table K shows a summary of the primary clinical endpoint (rTNSS) andsecondary clinical endpoints (iTNSS, rTOSS, onset of action and RQLQ)observed during this Phase III study. For comparison of the combinationtherapy against a monotherapy, a p-value below 0.05 is consideredstatistically significant.

TABLE K Primary Clinical Treatment Endpoint Secondary Clinical endpointsArm rTNSS iTNSS rTOSS Onset of Action RQLQ TP-1 vs −0.98 p < 0.0001*−0.93 p < 0.0001* −0.49 p = 0.0014* 15 min −0.43 p = 0.0001 PboStatistically significant at all time points TP-1 vs −0.61 p = 0.0029*−0.50 p = 0.0050* −0.09 p = 0.5423 NA −0.28 p = 0.0105 GO-2 TP-1 vs−0.39 p = 0.058 −0.36 p = 0.0413* −0.19 p = 0.2113 NA −0.20 p = 0.0692GM-2 GO-2 vs −0.37 p = 0.075 −0.42 p = 0.0177* −0.40 p = 0.0100statistically −0.15 p = 0.1659 Pbo significant at 45 mins only GM-2 vs−0.59 p = 0.004 −0.57 p = 0.0017* −0.30 p = 0.0510 Not statistically−0.23 p = 0.0345 Pbo significant at all time points *indicatesstatistical significance.

As can be seen from Table K, the combination of mometasone fuorate andolopatadine hydrochloride, when administered twice daily (TP-1) isstatistically superior to placebo (p<0.0001) for the primary endpoint,change in rTNSS from baseline, and is statistically superior toolopatadine hydrochloride monotherapy (GO-2). The secondary endpointswere also statistically significant for combination of mometasonefuorate and olopatadine hydrochloride, when administered twice daily(TP-1), supportive of its efficacy in the treatment of seasonal allergicrhinitis (SAR).

The combination of mometasone fuorate and olopatadine hydrochloride,when administered twice daily (TP-1) also exhibited a faster (rapid)onset of action (an onset of action within 15 minutes), as measured byiTNSS, when compared to olopatadine hydrochloride monotherapy ormometasone fuorate monotherapy.

All TEAEs were mild to moderate. Dysgeusia (3.3%) and headache (0.7%)reported as adverse events for the combination of mometasone fuorate andolopatadine hydrochloride administered twice daily (BID).

The pharmacokinetics (PK) of TP-1 were measured for a subset of patientsin the phase III clinical study on day 1 and day 8 (steady state). ThePK results for patients receiving TP-1 are provided below.

Olopatadine Mometasone furoate PK parameter Day 1 Day 8 PK parameter Day1 Day 8 C_(max) (ng/mL) n = 26 n = 25 C_(max) (pg/mL) n = 26 n = 26 Mean(SD) 19.82 (6.36) 19.80 (7.01) Mean (SD) 6.78 (2.71) 9.92 (3.74) CV %32.12 35.39 CV % 39.96 37.69 Min-Max 8.70-31.60 9.67-37.30 Min-Max2.67-12.80 3.58-16.10 Geo Mean 18.77 (35.61) 18.70 (35.34) Geo Mean 6.27(42.80) 9.17 (43.88) (Geo CV %) (Geo CV %) AUC_(tau) n = 26 n = 24AUC_(tau) n = 26 n = 25 (ng*hr/mL) (pg*hr/mL) Mean (SD) 75.48 (20.02)88.77 (23.87) Mean (SD) 28.56 (13.33) 58.40 (27.00) CV % 26.53 26.89 CV% 46.67 46.23 Min-Max 39.33-116.80 53.35-138.34 Min-Max 12.11-72.54 25.68-124.05 Geo Mean 72.90 (27.67) 85.74 (27.54) Geo Mean 26.16 (43.51)52.67 (49.48) (Geo CV %) (Geo CV %) T_(max) (hour) n = 26 n = 26 T_(max)(hour) n = 26 n = 26 Median (range) 1.00 (0.25-3) 1.00 (0.25-2) Median(range) 1.00 (0.25-2) 1.00 (0.25-2)

Example 6 Phase III Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Human Patients with SAR, Falland Mountain Cedar Season

This study was a double-blind, randomized, parallel-group, comparativestudy to evaluate the efficacy, safety and tolerability of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray compared with a placebo nasal spray and individual monotherapyformulations of olopatadine hydrochloride nasal spray and mometasonefuroate nasal spray, in subjects (12 years of age and older) withseasonal allergic rhinitis (SAR), fall and mountain cedar season.

Study Objectives

-   -   To compare the efficacy of mometasone furoate and olopatadine        hydrochloride nasal spray twice daily with the placebo nasal        spray and with the individual constituent monotherapies at the        same dose in the same vehicle over 14 days of study treatment.    -   To assess the safety and tolerability of individual treatment        arms.

TABLE L Investigational products and their administration CodeInvestigational product(s) Administration TP-1 Olopatadinehydrochloride + Twice daily (BID) in mometasone furoate (665 μg +morning and evening 25 μg) nasal spray GO-2 Olopatadine hydrochlorideTwice daily (BID) in (665 μg) nasal spray morning and evening GM-2Mometasone furoate (25 Twice daily (BID) in μg) nasal spray morning andevening

Sample Size:

A total of 1,176 randomized subjects (˜294 subjects per treatment arm)were enrolled in the study. For this study, the subject population isadult and adolescent subjects (12 years of age and older) with SAR whoexhibit symptoms of SAR during the fall allergy season to the relevantseasonal allergen (e.g., ragweed).

Study Design:

Subjects were randomized to treatment in a 1:1:1:1 ratio to thefollowing four treatment arms, at multiple study sites.

TABLE M Treatment Administration Using Two Identical Bottles of NasalSprays (2 sprays per nostril, total 4 sprays each bottle, per day)Morning Evening (AM) (PM) Code Treatment Arm 1^(st) bottle 2^(nd) bottleTP-1 Olopatadine hydrochloride 665 μg + Active Active mometasone furoate25 μg twice daily (BID) GO-2 Olopatadine hydrochloride nasal ActiveActive spray (665 μg) twice daily (BID) GM-2 Mometasone furoate, nasalspray (25 Active Active μg) twice daily (BID) Pbo Placebo nasal sprayPlacebo Placebo

This study consisted of four visits to the study site. After the initialscreening visit (Visit 1), subjects who met all study selection criteriawere required to undergo a single-blind placebo run-in period for 7-10days. Following the completion of the run-in period, eligible subjectsmeeting the randomization criteria were enrolled and randomized to oneof the four treatment arms. Subjects were dispensed medication as perthe randomization list. Randomized subjects were required to undergo a 2week (14 days) treatment period as per the protocol to assess theefficacy and safety of the assigned treatment. Subjects were instructedto record the symptom scores in a symptom assessment diary.

Key Evaluation Criteria (Clinical Endpoints): Primary Endpoint

-   -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS (reflective TNSS) over the 14-day treatment        period.

Secondary Endpoints

-   -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS (instantaneous TNSS) over the 14 day treatment        period.    -   Change from baseline in average AM and PM subject-reported        12-hour rTOSS (reflective TOSS) over the 14-day treatment        period.    -   Onset of action for each treatment are assessed by comparing the        change from baseline in post-treatment iTNSS between each active        treatment and placebo at defined time points (prior to first        dose (pre-dose), 15 min, 30 min, 45 min, 60 min, 90 min, 120        min, 150 min, 180 min, 210 min, and 240 min) after the first        study treatment for 4 hours.    -   Change from baseline in the overall Rhinoconjunctivitis Quality        of Life questionnaire (RQLQ)—Standardized Activities (RQLQ(S))        score on Day 15 (Visit 4) for the Full Analysis Set (FAS).

Tertiary Efficacy Endpoints Nasal Symptoms:

-   -   Change from baseline in AM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        nasal symptoms over the 14-day treatment period (AM, PM and        average of AM and PM).    -   Change from baseline in subject-reported instantaneous        individual nasal symptoms over the 14-day treatment period (AM,        PM and average of AM and PM).    -   Change from baseline in average AM and PM subject-reported rTNSS        and iTNSS for each day.    -   Change from baseline in AM subject-reported rTNSS and iTNSS for        each day.    -   Change from baseline in PM subject-reported rTNSS and iTNSS for        each day.

Ocular Symptoms:

-   -   Change from baseline in average AM and PM subject-reported iTOSS        (instantaneous TOSS) over the 14-day treatment period.    -   Change from baseline in AM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        ocular symptoms over the 14-day treatment period (AM, PM and        average AM and PM).    -   Change from baseline in subject-reported instantaneous        individual ocular symptoms over the 14-day treatment period (AM,        PM and average AM and PM).    -   Change from baseline in average of the AM and PM        subject-reported rTOSS and iTOSS for each day.    -   Change from baseline in AM subject-reported rTOSS and iTOSS for        each day.    -   Change from baseline in PM subject-reported rTOSS and iTOSS for        each day.        The non-nasal symptoms are assessed in a similar manner to the        ocular symptoms above.

Physician Assessed Nasal Symptom Score (PNSS), RhinoconjuntivitisQuality of Life Questionnaire Standardized Activities (RQLQ(S)), andRhinitis Control Assessment Test (RCAT):

-   -   Change from baseline in PNSS and physician assessed individual        nasal symptoms at Day 15 (Visit 4).    -   Change from baseline in individual domains of the RQLQ(S) at Day        15 (Visit 4) for the FAS.    -   Change from baseline in overall RQLQ(S) score and individual        domains of the RQLQ(S) at Day 15 (Visit 4) for the RQLQ(S)        Analysis Set.    -   Change from baseline in the RCAT at Day 15 (Visit 4).    -   Change from baseline in individual domains of the RCAT at Day 15        (Visit 4).

Results

Table N shows a summary of the primary clinical endpoint (rTNSS) andsecondary clinical endpoints (iTNSS, rTOSS, onset of action and RQLQ)observed during this Phase III study. For comparison of the combinationtherapy against a monotherapy, a p-value below 0.05 is consideredstatistically significant.

TABLE N Primary Clinical Secondary Clinical Endpoints Treatment EndpointOnset of Arm rTNSS iTNSS rTOSS Action RQLQ TP-1 vs. −1.09 −0.94 −0.52 15minutes. −0.45 Pbo (p < 0.001)* (p < 0.001)* (p = 0.001)* Statistically(p = 0.0001)* significant at all time points. TP-1 vs. −0.44 −0.41 −0.17N/A −0.31 GO-2 (p = 0.028)*  (p = 0.0035)* (p = 0.297)  (p = 0.0090)*TP-1 vs. −0.47 −0.51 −0.35 N/A −0.09 GM-2 (p = 0.019)* (p = 0.008)* (p =0.030)* (p = 0.423)  GO-2 vs. −0.64 −0.54 −0.35 15 minutes. −0.14 Pbo (p= 0.001)* (p = 0.005)* (p = 0.029)* Statistically (p = 0.221) significant at all time points. GM-2 vs. −0.62 −0.44 −0.17 Not −0.36 Pbo(p = 0.002)* (p = 0.023)* (p = 0.282) statistically (p = 0.0024)*significant at any time point. *indicates statistical significance

As can be seen from Table N, the combination of mometasone fuorate andolopatadine hydrochloride, when administered twice daily (TP-1) isstatistically superior to placebo (p<0.0001) for the primary endpoint,change in rTNSS from baseline, and is statistically superior toolopatadine hydrochloride monotherapy (GO-2) and mometasone fuoratemonotherapy (GM-2). The secondary endpoints were also statisticallysignificant for combination of mometasone fuorate and olopatadinehydrochloride, when administered twice daily (TP-1), supportive of itsefficacy in the treatment of seasonal allergic rhinitis (SAR).

Table N2 shows the least squares mean difference in individualreflective and instantaneous nasal symptoms scores for the TP-1 groupversus the placebo group.

TABLE N2 Least Squares Mean Difference in Individual Reflective andInstantaneous Nasal Symptom Scores with TP-1 versus Placebo Leastsquares mean difference (97.5% confidence interval) P value ReflectiveRhinorrhea −0.30 (−0.41, −0.19) <0.001 Nasal congestion −0.20 (−0.30,−0.09) <0.001 Nasal itching −0.23 (−0.34, −0.12) <0.001 Sneezing −0.41(−0.53, −0.29) <0.001 Instantaneous Rhinorrhea −0.29 (−0.39, −0.18)<0.001 Nasal congestion −0.19 (−0.29, −0.09) <0.001 Nasal itching −0.21(−0.32, −0.10) <0.001 Sneezing −0.29 (−0.41, −0.18) <0.001

The combination of mometasone fuorate and olopatadine hydrochloride,when administered twice daily (TP-1) also exhibited a faster (rapid)onset of action (an onset of action within 15 minutes), as measured byiTNSS, when compared to olopatadine hydrochloride monotherapy ormometasone fuorate monotherapy.

All TEAEs were mild to moderate. Dysgeusia (3.8%) nasal discomfort (1%)and urinary tract infection (1%) were reported adverse events for thecombination of mometasone fuorate and olopatadine hydrochlorideadministered twice daily (BID).

Example 7 Phase III Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Human Patients

The study is a double-blind, randomized, parallel-group, comparativestudy to evaluate the long-term safety, efficacy, and tolerability of afixed dose combination of mometasone furoate and olopatadinehydrochloride nasal spray compared with two placebo nasal sprays, insubjects (12 years of age and older) with perennial allergic rhinitis(PAR).

Study Objectives

To compare the long-term safety and tolerability of mometasone furoateand olopatadine hydrochloride nasal spray twice daily with two placebonasal sprays at the same dose in the same vehicle over 52 weeks of studytreatment in subjects with PAR.

A secondary objective is to evaluate the long-term efficacy of a fixeddose combination of mometasone furoate and olopatadine hydrochloridenasal spray compared with a placebo nasal spray formulations (pH=3.7) insubjects with PAR.

Key Subject Selection Criteria:

-   -   Male and non-pregnant females aged ≥12 years.    -   A history of PAR for a minimum of 2 years and a positive skin        prick test to at least 1 relevant allergen.    -   An AM subject-reported Reflective Total Nasal Symptom Score        (rTNSS)≥5 out of a possible 12 and a congestion score ≥2 for the        morning (AM) assessment at the Screening Visit (Visit 1).    -   At the end of the placebo run-in period, to be eligible for        randomization, the subject had not experienced an AE that would        result in not meeting the Screening inclusion criteria.    -   Minimum AM subject-reported rTNSS of an average of 5 (out of a        possible 12) during the last 4 days of the run-in period (last 4        consecutive AM assessments from the Day 3 AM assessment to the        AM assessment on the day of randomization)    -   Had an AM subject-reported reflective nasal congestion score of        an average 2 or greater during the last 4 days of the run-in        period (last 4 consecutive AM assessments from the Day 3 AM        assessment to the AM assessment on the day of randomization)

Study Design:

A total of 601 randomized subjects were enrolled in the study. Subjectswere randomized to treatment in a 4:1:1 ratio to 3 treatment groups, atmultiple site. The treatment groups are provided in Table I below.

TABLE I Investigational products and their administration CodeInvestigational product(s) Administration TP-1 Olopatadinehydrochloride + mometasone Twice daily (BID) in furoate (665 μg + 25 μg)nasal spray morning and evening Pbo-1 Placebo nasal spray, pH 3.7Placebo - Twice daily (BID) in morning and evening Pbo-2 Placebo nasalspray, pH 7.0 Placebo - Twice daily (BID) in morning and evening

This study consisted of twelve visits to the study site. After theinitial screening visit (Visit 1), subjects who met all study selectioncriteria underwent a single-blind placebo run-in period for 7-10 days.Following the completion of the run-in period, eligible subjects meetingthe randomization criteria were enrolled and randomized to one of thethree treatment arms. Randomized subjects underwent a 52 week treatmentperiod as per the protocol to assess the efficacy and safety of theassigned treatment.

Key Evaluation Criteria (Clinical Endpoints):

Primary Endpoints

-   -   Proportion of subjects with treatment-emergent adverse events        (TEAEs).    -   Proportion of subjects with treatment-related TEAEs.    -   Incidence, type, and severity of the TEAEs after 30 weeks of        study treatment.    -   Incidence, type, and severity of the TEAEs after 52 weeks of        study treatment.    -   Clinical laboratory assessments (hematology, serum biochemistry,        and urinalysis) at baseline, Week 30, and Week 52.    -   Vital signs, physical examinations (PE), and focused ears, nose,        and throat (ENT) and eye examinations at baseline, Week 30, and        Week 52.

Secondary Endpoints

Efficacy Endpoints

-   -   Change from baseline in the average AM subject-reported rTNSS        over the first 6, 30, and 52 weeks of treatment.    -   Change from baseline in the average AM subject-reported        instantaneous Total Nasal Symptom Score (iTNSS) over the first        6, 30, and 52 weeks of treatment.    -   Change from baseline in the overall Rhinoconjunctivitis Quality        of Life Questionnaire—Standardized Activities (RQLQ(S)) score at        Weeks 6, 30, and 52 for the Full Analysis Set (FAS).

Other Efficacy Endpoints

Other endpoints included other assessments of AM subject-reportedindividual nasal symptoms, AM subject-reported rTNSS and iTNSS frombaseline to the end of each treatment week, Physician-assessed NasalSymptom Score and physician-assessed individual nasal symptoms,individual domains of the RQLQ for the FAS population, and change frombaseline in the Rhinitis Control Assessment Test and individual domainsof Rhinitis Control Assessment Test.

Data Sets Analyzed

-   -   The Full Analysis Set (FAS) consisted of all subjects who were        randomized and received at least one dose of investigational        product and had at least one post-baseline efficacy assessment.        This was the primary analysis set for efficacy analyses.    -   The Per Protocol Set (PPS) consisted of the subset of the FAS        who did not meet criteria for PPS exclusion. The PPS was a        secondary analysis set for the efficacy analyses (except for        RQLQ(S)).    -   The Safety Analysis Set (SAS) consisted of all subjects who took        at least one dose of study medication following randomization,        and was used for all safety analyses.    -   The RQLQ(S) Analysis Set consisted of all English-speaking        subjects ≥18 years old with impaired quality of life at baseline        as defined by RQLQ(S) Score at the Randomization Visit (Visit 2)        of 3.0 or greater

Efficacy Analysis

Efficacy analysis was conducted on the FAS and PPS.

Change from baseline in average AM rTNSS and iTNSS over the first 6, 30,and 52 weeks of treatment was analyzed using an analysis of covariance(ANCOVA) model adjusting for study treatment group, site, and baseline(defined as the average of the last 4 consecutive AM assessments duringthe last 4 days of the run-in period from the Day −3 AM assessment tothe AM assessment on the day of randomization). Least squares means(LSMs) of the treatment differences and associated 95% confidenceintervals (95% CIs) and p-values were presented.

Changes from baseline in rTNSS and iTNSS at the end of each week oftreatment and changes from baseline in individual nasal symptom scoresover the first 6, 30, and 52 weeks (and at the end of each treatmentweek) of the treatment period were analyzed in a similar manner asdescribed above.

Changes from baseline in RQLQ(S) at Weeks 6, 30, and 52 were analyzedfor the FAS and the RQLQ(S) Analysis Set using ANCOVA models adjustingfor study treatment group, site, and baseline RQLQ(S) (linear,continuous covariate). At each time-point, only completers of therespective visit were analyzed.

The analyses of RCAT results were similar to the RQLQ(S) analyses exceptthat it was performed only for the FAS.

Safety Analysis

Adverse events occurring after the first dose of randomized studymedication were defined as TEAEs.

The safety endpoints related to AEs were:

-   -   Proportion of subjects with TEAEs.    -   Proportion of subjects with treatment-related TEAEs.    -   Incidence, type, and severity of the TEAEs after 30 weeks of        study treatment.    -   Incidence, type, and severity of the TEAEs after 52 weeks of        study treatment.

Results Safety Analysis

The table below summarizes the safety analysis for the three treatmentgroups over the 52 week administration period.

Pbo-1 Pbo-2 Safety Analysis TP-1 (pH = 3.7) (pH = 7.0) Subjects with aleast 203 (52%) 41 (41%) 54 (54%) one TEAE: n (%) TEAEs resulting in 15(3.8%) 2 (2.0%) 3 (3.0%) discontinuation: n (%) SAEs (all 7 (1.5%) 2(2.0%) 3 (1.5%) considered not related)

As can be seen, there was no meaningful differences between the threetreatment groups. The majority of TEAEs were mild to moderate severityand considered “not related” by the investigator. The TP-1 treatment wassafe and well tolerated, with safety profiles consistent with thoseexpected for the individual monotherapy components. No deaths werereported during the study.

Efficacy Analysis

The table below summarizes the results for the efficacy endpoint: nasalsymptoms average AM Reflective Total Nasal Symptoms (rTNSS, last 12hours) (full set analysis, FAS).

TP-1 vs. Pbo-1 (pH = 3.7) 6 weeks 30 weeks 52 Weeks N (TP-1/Pbo-1)319/99 391/99 391/99 Treatment −0.81   −0.96   −0.91   Difference 95% Cl−1.29, −0.32 −1.41, −0.50 −1.35, −0.47 p-Value 0.0012* <0.0001* <0.0001**Statistically Significant

As can be seen, TP-1 demonstrated a statistically significant andmeaningful improvement in rTNSS versus Pbo-1 (pH=3.7) over the first 6,30 and 52 weeks of the study.

The table below summarizes the results for the efficacy endpoint: nasalsymptoms average AM Instantaneous Total Nasal Symptoms (iTNSS, last 12hours) (full set analysis, FAS).

TP-1 vs. Pbo-1 (pH = 3.7) 6 weeks 30 weeks 52 Weeks N (TP-1/Pbo-1)319/99 391/99 391/99 Treatment −0.66   −0.83   −0.75   Difference 95% Cl−1.12, −0.20 −1.26, −0.39 −1.17, −0.33 p-Value 0.0053* 0.0002* 0.0005**Statistically Significant

As can be seen, TP-1 demonstrated a statistically significant andmeaningful improvement in iTNSS versus Pbo-1 (pH=3.7) over the first 6,30 and 52 weeks of the study.

The table below summarizes the results for the Quality of Life Endpoint:RQLQ (S) (full set analysis, FAS).

TP-1 vs. Pbo-1 (pH = 3.7) 6 weeks 30 weeks 52 Weeks N (TP-1/Pbo-1)371/95 322/84 286/72 Treatment −0.42   −0.33   −0.04   Difference 95% Cl−0.70, −0.14 −0.60, −0.05 −0.34, −0.26 p-Value 0.0035* 0.0186* 0.7902*Statistically Significant

As can be seen, TP-1 demonstrated a statistically significant andmeaningful improvement in RQLQ (S) versus Pbo-1 (pH=3.7) over the first6 and 30 weeks of the study.

Examples 8 and 9 Suspension Compositions Containing Mometasone Furoate,Olopatadine HCl and Carboxymethylcellulose Sodium

Example 8 Example 9 SN Ingredient (% w/w) (% w/w) 1 Mometasone Furoatemonohydrate 0.050 0.025 Eq. to Mometasone furoate 2 OlopatadineHydrochloride 0.665 0.665 3 Avicel RC 591 (Microcrystalline 1.200 1.200Cellulose and Carboxymethylcellulose Sodium) 4 Benzalkonium chloride(50% solution) 0.040 0.040 5 Carboxymethylcellulose Sodium 0.500 0.500(Cekol 2000 P) 6 Sodium chloride 0.410 0.410 7 Edetate disodium 0.0100.010 8 Dibasic sodium phosphate heptahydrate 0.940 0.940 9 Polysorbate80 0.010 0.010 10 Sodium Hydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S.Q.S. 12 Water for injection Q.S. Q.S. Observations Physical observationon standing for 24 No phase No phase hours separation separationobserved observed Mean Particle size by microscopy Below 15 Below 15 μm.μm.

Manufacturing Procedure:

-   -   1. Avicel RC-591 was added in water for injection with        homogenization and allowed to hydrate.    -   2. Carboxymethylcellulose Sodium was dispersed in water for        injection and added to step −1.    -   3. Dibasic sodium phosphate heptahydrate, Sodium chloride,        Edetate disodium and Olopatadine were dissolved in water. The pH        was adjusted to 2.8-3.2 with Hydrochloric acid.    -   4. Step-3 was added to Step-1 with homogenization.    -   5. Polysorbate 80 was dissolved in water for injection.        Mometasone Furoate monohydrate was added and stirred to form        slurry.    -   6. Step-5 was added to Step-4 with homogenization.    -   7. Benzalkonium chloride was dissolved in water for injection.    -   8. Step-7 was added to Step-6 with homogenization.    -   9. The pH was checked and adjusted to 3.5-3.9 with HCl and the        total weight was adjusted with Water for injection. The        osmolality of the composition was about 250-350 mOsm/kg.        The composition was subjected to stability studies at different        conditions. The results of the same are as follows:        Container details: Sprayer containing HDPE bottle crimped with        pump and fitted with an actuator and can.

Stability Study Data Initial 3 months 6 months Test Ex. 8 Ex. 9 Ex. 8Ex. 9 Ex. 8 Ex. 9 Stability condition (25° C. ± 2° C. & 60% RH ± 5% RH)pH 3.61 3.69 3.73 3.78 3.81 Osmolality (mOsm)* 310 308 299 298 302 311Viscosity (cps)** 32.5 42.5 42.3 40.6 40.9 Weight per ml (g/ml) 1.011.021 1.024 1.029 1.019 Assay of mometasone 101 102.4 99.1 99.3 98.297.2 furoate (% w/w) Assay of olopatadine 98.2 99.9 97.3 99.1 97.8 97.9hydrochloride (% w/w) Related substances for mometasone furoate ImpurityDMCF (%) 0.02 0.03 0.09 0.10 0.14 0.17 Any other impurity (%) 0.04 0.040.03 Total impurities (%) 0.09 0.23 0.29 0.31 0.34 Related substancesfor olopatadine hydrochloride Olopatadine E-isomer (%) 0.08 0.07 0.090.09 Any other impurity (%) 0.03 0.04 0.09 0.12 0.11 0.11 Totalimpurities (%) 0.15 0.16 0.20 0.25 0.37 0.38 Spray Pattern (at 6 cm)Major Axis (mm) 52 60 63 59 61 Minor Axis (mm) 43 47 49 53 49 51Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet size distribution (at 6 cm)D₁₀ (μm) 18.91 19.45 19.26 19.70 19.33 18.88 D₅₀ (μm) 36.39 37.61 35.9637.34 39.28 37.85 D₉₀ (μm) 72.46 76.44 70.29 75.78 85.42 72.07 SPAN 1.471.51 1.42 1.5 1.67 1.46 Stability condition (40° C. ± 2° C. & 75% RH ±5% RH) pH 3.61 3.68 3.72 3.59 3.68 Osmolality (mOsm) 310 308 298 306 305299 Viscosity (cps) 32.5 45.2 42.6 41.8 41.5 Weight per ml (g/ml) 1.011.023 1.019 1.026 1.025 Assay of mometasone 101 102.4 99.8 100.4 98.398.4 furoate (%) Assay of oloptadine 98.2 99.9 99.3 102.5 98.7 99.7hydrochloride (%) Related substances for mometasone furoate ImpurityDMCF (%) 0.02 0.03 0.14 0.20 0.25 0.25 Any other impurity (%) 0.04 0.040.04 0.03 0.03 0.04 Total impurities (%) 0.09 0.25 0.39 0.40 0.46Related substances for olopatadine hydrochloride Olopatadine E-isomer(%) 0.08 0.07 0.08 0.08 0.09 Any other impurity (%) 0.03 0.04 0.21 0.180.31 0.30 Total impurities (%) 0.15 0.16 0.32 0.36 0.68 0.64 SprayPattern (at 6 cm) Major Axis (mm) 52 52 61 58 58 58 Minor Axis (mm) 4347 50 49 48 49 Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet sizedistribution (at 6 cm) D₁₀ (μm) 18.91 19.45 19.49 19.27 18.05 18.09 D₅₀(μm) 36.39 37.61 35.29 34.68 36.19 36.12 D₉₀ (μm) 72.46 76.44 64.6663.49 71.89 70.06 SPAN 1.47 1.51 1.28 1.27 1.50 1.44 *Determined byAdvanced Instruments Osmometer (Model 3250). **Determined by Brookfieldviscometer.

Examples 10 and 11 Suspension Compositions Containing MometasoneFuroate, Olopatadine HCl and Xanthan Gum

Example 10 Example 11 SN Ingredient ( % w/w) ( % w/w) 1 MometasoneFuroate monohydrate 0.050 0.025 Eq. to Mometasone furoate 2 OlopatadineHCl 0.665 0.665 3 Avicel RC 591 (Microcrystalline 1.000 1.000 Celluloseand Carboxymethylcellulose Sodium) 4 Benzalkonium chloride (50%solution) 0.040 0.040 5 Xantural 75 (Xanthan Gum) 0.300 0.300 6 Sodiumchloride 0.410 0.410 7 Edetate disodium 0.010 0.010 8 Dibasic sodiumphosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10Sodium Hydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S. Q.S. 12 Water forinjection Q.S. Q.S. Observations Physical observation on standing for 24No phase No phase hours separation separation observed observed MeanParticle size by microscopy Below 15 Below 15 μm. μm.

Manufacturing Procedure:

-   -   1. Avicel RC-591 was added in Water for injection with        homogenization and allowed to hydrate.    -   2. Xanthan gum was dispersed in Water for injection and added to        step −1.    -   3. Dibasic sodium phosphate heptahydrate, Sodium chloride,        Edetate disodium and Olopatadine were dissolved in water. The pH        was adjusted to 2.8-3.2 with Hydrochloric acid.    -   4. Step-3 was added to Step-1.    -   5. Polysorbate 80 was dissolved in water for injection.        Mometasone Furoate monohydrate was added to it and stirred to        form slurry.    -   6. Step-5 was added to Step-4 with homogenization.    -   7. Benzalkonium chloride was dissolved in water for injection.    -   8. Step-7 was added to Step-6 with homogenization.    -   9. The pH was checked and adjusted to 3.5-3.9 with HCl and the        weight was adjusted with water for injection. The osmolality of        the composition was about 250-350 mOsm/kg.    -   The composition was subjected to stability studies at different        conditions. The results of the same are as follows:        Container details: Sprayer containing HDPE bottle crimped with        pump and fitted with a actuator and cap

Stability Study Results Initial 3 months 6 months Test Ex. 10 Ex. 11 Ex.10 Ex. 11 Ex. 10 Ex. 11 Stability condition (25° C. ± 2° C. & 60% RH ±5% RH) pH 3.65 3.67 3.78 3.65 3.70 3.62 Osmolality (mOsm) 307 312 302316 308 308 Viscosity (cps) 124.2 129.1 127.9 129.9 126.2 126.8 Weightper ml (g/ml) 1.015 1.022 1.02 1.023 1.02 1.019 Assay of mometasone 99.9102.8 102.2 99.0 98.7 100.4 furoate (%) Assay of olopatadine 99.2 100.799.7 99.7 99.4 99.6 hydrochloride (%) Related substances for mometasonefuroate Impurity DMCF (%) 0.02 0.02 0.04 0.05 0.03 0.05 Any otherimpurity (%) 0.03 0.04 0.03 0.04 Total impurities (%) 0.11 0.10 0.150.16 0.12 0.16 Related substances for olopatadine hydrochlorideOlopatadine E-isomer (%) 0.08 0.07 0.09 0.11 0.11 0.10 Any otherimpurity (%) 0.03 0.04 0.05 0.05 0.08 0.08 Total impurities (%) 0.180.15 0.24 0.20 0.33 0.33 Spray Pattern (at 6 cm) Major Axis (mm) 46 5959 56 54 Minor Axis (mm) 38 47 44 35 43 Ellipticity 1.2 1.3 1.4 1.6 1.3Droplet size distribution (at 6 cm) D₁₀ (μm) 21.58 21.03 20.95 20.2718.73 18.34 D₅₀ (μm) 40.44 39.79 37.86 37.93 36.66 36.16 D₉₀ (μm) 78.2577.55 74.07 74.93 70.63 70.99 SPAN 1.40 1.42 1.40 1.44 1.41 1.45Stability condition (40° C. ± 2° C. & 75% RH ± 5% RH) pH 3.65 3.67 3.703.77 3.78 3.65 Osmolality (mOsm) 307 312 309 305 302 316 Viscosity (cps)124.2 129.1 129.6 124.3 127.9 129.9 Weight per ml (g/ml) 1.015 1.0221.017 1.027 1.022 1.020 Assay of mometasone 99.9 102.8 101.7 100.6 99.698.9 furoate (%) Assay of oloptadine 99.2 100.7 99.9 99.4 99.7 99.9hydrochloride (%) Related substances for mometasone furoate ImpurityDMCF (%) 0.02 0.02 0.10 0.12 0.10 0.12 Any other impurity (%) 0.03 0.030.02 0.03 0.05 0.03 Total impurities (%) 0.11 0.10 0.20 0.22 0.18 0.21Related substances for olopatadine hydrochloride Olopatadine E-isomer(%) 0.08 0.07 0.12 0.13 0.11 0.11 Any other impurity (%) 0.03 0.04 0.060.06 0.12 0.12 Total impurities (%) 0.18 0.15 0.26 0.26 0.41 0.40 SprayPattern (at 6 cm) Major Axis (mm) 46 46 56 58 54 55 Minor Axis (mm) 3838 45 49 34 43 Ellipticity 1.2 1.2 1.3 1.2 1.6 1.3 Droplet sizedistribution (at 6 cm) D₁₀ (μm) 21.58 21.03 20.67 23.16 19.13 19.16 D₅₀(μm) 40.44 39.79 38.06 39.08 37.34 37.26 D₉₀ (μm) 78.25 77.55 75.6369.37 72.36 72.49 SPAN 1.40 1.42 1.44 1.19 1.42 1.43

Comparative Examples A and B Suspension Composition ContainingMometasone Furoate, and Olopatadine HCl

Example (% w/w) SN Ingredient A B 1 Mometasone Furoate monohydrate 0.0500.050 Eq. to Mometasone furoate 2 Olopatadine HCl 0.665 0.665 3 AvicelRC 591 (Microcrystalline Cellulose 1.00 1.00  and Carboxymethylcellulose Sodium) 4 Benzalkonium chloride (50% solution) 0.040 0.040 5Carboxymethylcellulose Sodium 0.00 0.150 (Cekol 2000 P) 6 Sodiumchloride 0.410 0.410 7 Edetate disodium 0.010 0.010 8 Dibasic sodiumphosphate heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10Sodium Hydroxide Q.S. Q.S. 11 Hydrochloric acid Q.S. Q.S. 12 Water forinjection Q.S. Q.S. Observations pH 3.7 3.7  Physical observation onstanding for 24 Phase Phase hours separation separation observedobserved

Manufacturing Procedure:

The manufacturing procedure as mentioned in Example 8 was followed.

Comparative Examples C and D Suspension Composition ContainingMometasone Furoate and Olopatadine HCl

Example (% w/w) SN Ingredient C D 1 Mometasone Furoate monohydrate 0.0500.050 Eq. to Mometasone furoate 2 Olopatadine HCl 0.665 0.665 3 AvicelRC 591 (Microcrystalline Cellulose 1.000 1.000 and Carboxymethylcellulose Sodium) 4 Benzalkonium chloride (50% solution) 0.040 0.040 5Xantural 75 (Xanthan Gum) 0.00  0.20  6 Sodium chloride 0.410 0.410 7Edetate disodium 0.010 0.010 8 Dibasic sodium phosphate heptahydrate0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium Hydroxide Q.S. Q.S.11 Hydrochloric acid Q.S. Q.S. 12 Water for injection Q.S. Q.S.Observations pH 3.73  3.70  Physical observation on standing for 24Phase Phase hours separation separation observed observed

Manufacturing Procedure:

The manufacturing procedure as mentioned in Example 10 was followed.

Example 12 Pharmacokinetics of Olopatadine in a Fixed Dose Combinationof Mometasone Furoate and Olopatadine Hydrochloride Nasal Spray

The pharmacokinetics of olopatadine in a fixed dose combination ofmometasone furoate and olopatadine hydrochloride nasal spray wasevaluated in a clinical trial. The clinical trial was a randomized,single-center, single-dose, open-label, three-period, six-sequence,cross-over study to evaluate three treatments administered as a nasalspray. The three treatments included a combination of mometasone furoateand olopatadine hydrochloride nasal spray, olopatadine hydrochloridenasal spray and PATANASE® nasal spray.

Subjects were randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1ratio with all subjects receiving single doses of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray, olopatadine hydrochloride nasal spray, and PATANASE® nasal spray.The study consisted of a screening visit, 3 single-dose treatmentperiods with washout periods of 7 to 14 days between dosing in eachtreatment period, an early withdrawal visit if applicable, and afollow-up telephone call (or visit) 1 to 7 days after completing thethird treatment period.

A total of 30 subjects were randomized to 1 of 6 treatment sequences andreceived at least 1 dose of study drug. All 30 subjects were included inthe safety analysis set and the pharmacokinetic subset. All but 2subjects completed the study per protocol. The safety analysis setconsisted of 30 subjects: 29, 29, and 30 subjects in the safety analysisset received a single dose of the fixed dose combination of mometasonefuroate and olopatadine hydrochloride nasal spray, olopatadinehydrochloride nasal spray, and PATANASE® nasal spray, respectively. Thepharmacokinetic subset consisted of 30 subjects: 29, 29, and 30 subjectsin the pharmacokinetic subset received a single dose of the fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray, olopatadine hydrochloride nasal spray, and PATANASE® nasal spray,respectively.

Quantifiable concentrations of olopatadine were observed until the lasttime point (48 hours). All 3 treatments were well tolerated. No subjectdied or reported a serious adverse event; and only one subjectdiscontinued due to a treatment-emergent adverse event (mildoropharyngeal pain) in this study. Treatment-emergent adverse events andtreatment-related treatment emergent adverse events were evenlydistributed across the 3 treatments. All treatment-emergent adverseevents were mild. There was no clinically significant effect of any ofthe treatments on laboratory values, vital sign measurements, or ECGparameters.

Example 13 Pharmacokinetics of Mometasone Furoate in a Fixed DoseCombination of Mometasone Furoate and Olopatadine Hydrochloride NasalSpray

The pharmacokinetics of mometasone furoate in a fixed dose combinationof mometasone furoate and olopatadine hydrochloride nasal spray wasevaluated in a clinical trial. The clinical trial was a randomized,single-center, single-dose, open-label, three-period, six-sequence,cross-over study to evaluate three treatments administered by nasalspray. The three treatments included a combination of mometasone furoateand olopatadine hydrochloride nasal spray, mometasone furoate nasalspray and Nasonex® nasal spray.

Subjects were randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1ratio with all subjects receiving single doses of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray, mometasone furoate nasal spray and Nasonex® nasal spray. Thestudy consisted of a screening visit, 3 single-dose treatment periodswith washout periods of 7 to 14 days between dosing in each treatmentperiod, an early withdrawal visit if applicable, and a follow-uptelephone call (or visit) 1 to 7 days after completing the thirdtreatment period.

A total of 30 subjects were randomized to 1 of 6 treatment sequences andreceived at least 1 dose of study drug. All 30 subjects were included inthe safety analysis set and the pharmacokinetic subset. All but 2subjects completed the study per protocol. The safety analysis setconsisted of 30 subjects: 29, 29, and 30 subjects in the safety analysisset received a single dose of the fixed dose combination of mometasonefuroate and olopatadine hydrochloride nasal spray, mometasone furoatenasal spray and Nasonex® nasal spray, respectively. The pharmacokineticsubset consisted of 30 subjects: 29, 29, and 30 subjects in thepharmacokinetic subset received a single dose of the fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray, mometasone furoate nasal spray and Nasonex® nasal sprayrespectively.

Quantifiable concentrations of mometasone furoate were observed untilthe last time point (72 hours). All 3 treatments were well tolerated. Nosubject died or reported a serious adverse event, or discontinued due toa treatment-emergent adverse event in this study. Treatment-emergentadverse events were evenly distributed across the 3 treatments. Alltreatment-emergent adverse events were mild. There was no clinicallysignificant effect of any of the treatments on laboratory values, vitalsign measurements, or ECG parameters.

Pharmacokinetic Parameters Therapy AUC_((0-t)) AUC_((0-infinity))C_(max) T_(max) Olopatadine in fixed 70.95 ng · h/mL 83.26 ng · h/mL17.27 ng/mL 1.00 hr dose combination of mometasone furoate andolopatadine hydrochloride nasal spray Mometasone furoate in 84.97 pg ·h/mL 103.77 pg · h/mL  10.81 pg/mL 1.00 hr fixed dose combination ofmometasone furoate and olopatadine hydrochloride nasal spray RelativeBioavailability of fixed dose combination of mometasone furoate andolopatadine hydrochloride nasal spray versus: Patanase ® 87.87 93.8084.68 — (Geometric mean ratio %) Nasonex ® 109.92 115.14 141.84 —(Geometric mean ratio %) olopatadine 86.92 92.83 86.63 — hydrochloride(Geometric mean ratio %) mometasone furoate 118.36 118.50 113.83 —(Geometric mean ratio %)

Example 14 Phase III Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Pediatric Patients

This study is a double blind, randomized, parallel-group, 12-week studyto evaluate the efficacy, safety, and tolerability of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray compared with a placebo nasal spray in pediatric subjects (aged 2to under 12 years) with perennial seasonal allergic rhinitis (PAR).

Study Objectives

To compare the efficacy of mometasone furoate and olopatadinehydrochloride nasal spray (administered as 1 spray per nostril twicedaily) with a placebo nasal spray for treatment in pediatric subjects(aged ≥2 to <12 years) with PAR.

A secondary objective is to compare the safety and tolerability ofmometasone furoate and olopatadine hydrochloride nasal spray with aplacebo nasal spray over 12 weeks of study treatment.

Key Subject Selection Criteria

-   -   Male or non-pregnant female subjects aged ≥2 to <12 years, as of        the Screening Visit (Visit 1).    -   Documented clinical history of PAR (≥12 months for subjects aged        ≥6 to <12 years, ≥6 months for subjects aged ≥2 to <6 years        preceding the Screening Visit [Visit 1]) with exacerbations        (clinical evidence of active symptoms). In the judgment of the        Investigator, the PAR must have been of sufficient severity to        have required treatment (either continuous or intermittent) in        the past and is expected to require treatment for the study        duration.    -   Documented positive skin prick test (wheal diameter at least 3        mm greater than negative control wheal) to at least one allergen        known to induce PAR. Documentation of a positive result within        12 months prior to the Screening Visit (Visit 1) is acceptable.        Positive allergen test for the subject that must be consistent        with the medical history of PAR. Additionally the subject is        expected to be exposed to the PAR allergen that he or she tested        positive for via the skin prick test for the entire duration of        the study.    -   A 12-hour rTNSS value of ≥6 (out of a possible 12) for the AM        assessment at the Screening Visit (Visit 1).

Study Design

A total of approximately 540 subjects (≥2 to <12 years) will berandomized in the study in a 2:1 ratio for a fixed dose combination ofmometasone furoate and olopatadine hydrochloride nasal spray (360subjects) versus placebo nasal spray (180 subjects).

The study will be 12 weeks in duration. The subject participation mayextend up to 13 to 14 weeks consisting of up to 7 to 10 days of ascreening/placebo run-in period and 12 weeks of treatment period withallowable window periods for the study visits. The treatment groups areprovided in the table below.

Investigational Products and their Administration

Investigational product(s) Administration Olopatadine hydrochloride +mometasone furoate 1 spray per nostril, (665 μg + 25 μg) nasal spray*twice daily (BID) in morning and evening Placebo nasal spray Placebo - 1spray per nostril twice daily (BID) in morning and evening *Each sprayprovides 665 μg olopatadine hydrochloride and 25 μg mometasone furoate.

Primary Endpoint:

-   -   Change from baseline in average AM and PM subject-reported        12-hour reflective Total Nasal Symptom Score (rTNSS) over the        first 4 weeks of treatment for subjects aged ≥6 to <12 years.

Secondary Endpoint(s):

-   -   Change from baseline in average AM and PM subject-reported        12-hour instantaneous Total Nasal Symptom Score (iTNSS) over the        first 4 weeks of treatment for subjects ≥6 to <12 years of age.    -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS over the first 4 weeks of treatment for subjects        ≥2 to <12 years of age.    -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS over the first 4 weeks of treatment for subjects        ≥2 to <12 years of age.    -   Change from baseline in the overall Pediatric        Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) score        at Week 4 between treatment groups.

Other Endpoint(s):

Nasal Symptoms:

TNSS—First 4 Weeks, Subjects Aged ≥6 to <12 Years:

-   -   Change from baseline in AM subject-reported rTNSS over the first        4 weeks of treatment.    -   Change from baseline in PM subject-reported rTNSS over the first        4 weeks of treatment.    -   Change from baseline in AM subject-reported iTNSS over the first        4 weeks of treatment.    -   Change from baseline in PM subject-reported iTNSS over the first        4 weeks of treatment.    -   Change from baseline in subject-reported reflective individual        nasal symptoms over the first 4 weeks of treatment period (AM,        PM and average of AM and PM).    -   Change from baseline in subject-reported instantaneous        individual nasal symptoms over the first 4 weeks of treatment        period (AM, PM and average of AM and PM).    -   Change from baseline subject-reported rTNSS and iTNSS for each        day (AM, PM and average of AM and PM).

TNSS—First 4 Weeks, Subjects Aged ≥2 to <6 Years:

-   -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS over the first 4 weeks of treatment for subjects        aged ≥2 to <6 years.    -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS over the first 4 weeks of treatment for subjects        aged ≥2 to <6 years.

TNSS—First 4 Weeks, Subjects Aged ≥2 to <12 Years:

-   -   Change from baseline in average AM and PM subject-reported        12-hour rTNSS over the first 4 weeks of treatment for subjects        aged ≥2 to <12 years.    -   Change from baseline in average AM and PM subject-reported        12-hour iTNSS over the first 4 weeks of treatment for subjects        aged ≥2 to <12 years.

Additional Total Nasal Symptom Score (TNSS) outcomes will be assessedfor the following (e.g. AM, PM, Individual symptoms):

-   -   12 weeks, subjects aged ≥6 to <12 years.    -   12 weeks, subjects aged ≥2 to <6 years.    -   12 weeks, subjects aged ≥2 to <12 years.

Physician Assessed Nasal Symptom Score (PNSS):

-   -   Change from baseline in PNSS and physician assessed individual        nasal symptoms at Weeks 4 and 12.

Pediatric Rhinoconjuntivitis Quality of Life Questionnaire (PRQLQ):

-   -   Individual domains of the PRQLQ at Weeks 4 and 12.

Example 15 Phase III Clinical Study of Fixed Dose Combination ofMometasone and Olopatadine Nasal Spray in Pediatric Patients

This study is a double blind, randomized, parallel-group 14 day study toevaluate the efficacy, safety, and tolerability of a fixed dosecombination of mometasone furoate and olopatadine hydrochloride nasalspray compared with a placebo nasal spray over 14 days in pediatricsubjects (aged 6 to under 12 years) with seasonal allergic rhinitis(SAR).

Study Objectives

To compare the efficacy of mometasone furoate and olopatadinehydrochloride nasal spray (administered as 1 spray per nostril twicedaily) with a placebo nasal spray for treatment in pediatric subjects(aged ≥6 to <12 years) with SAR.

A secondary objective is to compare the safety and tolerability ofmometasone furoate and olopatadine hydrochloride nasal spray with aplacebo nasal spray over the study period.

Key Subject Selection Criteria

-   -   Male or non-pregnant female subjects aged ≥6 to <12 years, at        the Screening Visit (Visit 1).    -   Documented clinical history of SAR (for at least 2 years        preceding the Screening Visit [Visit 1]) with exacerbations        (clinical evidence of active symptoms) during the study season        for the relevant seasonal allergen (tree/grass pollen). SAR must        have been of sufficient severity to have required treatment        (either continuous or intermittent) in the past, and in the        Investigator's judgment, is expected to require treatment        throughout the study period.    -   Demonstrated sensitivity to at least 1 seasonal allergen        (tree/grass pollen) known to induce SAR through a documented        positive skin prick test (wheal diameter at least 5 mm greater        than the negative control) to a relevant seasonal allergen.        Documentation of a positive result within 12 months prior to the        Screening Visit (Visit 1) is acceptable. The subject's positive        allergen must be consistent with the medical history of SAR.        Additionally, the subject is expected to be adequately exposed        to the SAR allergen that he/she has tested positive for the        entire duration of the study.    -   A 12-hour reflective Total Nasal Symptom Score (rTNSS) value of        ≥6 (out of a possible 12) for the morning (AM) assessment at the        Screening Visit (Visit 1).

Study Design

A total of approximately 450 subjects (≥6 to <12 years) will berandomized in the study in a 1:1 ratio for a fixed dose combination ofmometasone furoate and olopatadine hydrochloride nasal spray (225subjects) versus placebo nasal spray (225 subjects).

The treatment groups are provided in the table below.

Investigational Products and their Administration

Investigational product(s) Administration Olopatadine hydrochloride +mometasone furoate 1 spray per nostril, (665 μg + 25 μg) nasal spray*twice daily (BID) in morning and evening Placebo nasal spray Placebo - 1spray per nostril twice daily (BID) in morning and evening *Each sprayprovides 665 μg olopatadine hydrochloride and 25 μg mometasone furoate.

The subject participation may be 22 days up to 27 days with 7 to 10 daysof a screening/run-in period and 14 days of treatment period, withallowable window periods for the study visits.

Key Evaluation Criteria (Clinical Endpoints): Primary Endpoint

-   -   Change from baseline in average AM and PM subject-reported        12-hour reflective Total Nasal Symptom Score (rTNSS) over the 14        day treatment period.

Secondary Endpoint(s):

-   -   Change from baseline in average AM and PM subject-reported        12-hour instantaneous Total Nasal Symptom Score (iTNSS) over the        14 day treatment period.    -   Change from baseline in the overall Pediatric        Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) score        on Day 15 (Visit 4) between treatment groups.    -   Change from baseline in average AM and PM subject-reported        12-hour reflective Total Ocular Symptom Score (rTOSS) over the        14-day treatment period.

Other Efficacy Endpoint(s):

Nasal Symptoms

-   -   Change from baseline in AM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTNSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTNSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        nasal symptoms over the 14-day treatment period (AM, PM and        average of AM and PM).    -   Change from baseline in subject-reported instantaneous        individual nasal symptoms over the 14-day treatment period (AM,        PM and average of AM and PM).    -   Change from baseline in average AM and PM subject-reported rTNSS        and iTNSS for each day.    -   Change from baseline in AM subject-reported rTNSS and iTNSS for        each day.    -   Change from baseline in PM subject-reported rTNSS and iTNSS for        each day.

Ocular Symptoms:

-   -   Change from baseline in average AM and PM subject-reported        instantaneous Total Ocular Symptom Score (iTOSS) over the 14-day        treatment period.    -   Change from baseline in AM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in AM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported rTOSS over the        14-day treatment period.    -   Change from baseline in PM subject-reported iTOSS over the        14-day treatment period.    -   Change from baseline in subject-reported reflective individual        ocular symptoms over the 14-day treatment period (AM, PM, and        average AM and PM).    -   Change from baseline in subject-reported instantaneous        individual ocular symptoms over the 14-day treatment period (AM,        PM, and average AM and PM).    -   Change from baseline in average of the AM and PM        subject-reported rTOSS and iTOSS for each day.    -   Change from baseline in AM subject-reported rTOSS and iTOSS for        each day.    -   Change from baseline in PM subject-reported rTOSS and iTOSS for        each day.

Non-nasal symptoms will be assessed in a similar manner to the ocularsymptoms above (as described in the Statistical Analysis Plan [SAP]).

Physician Assessed Nasal Symptom Score (PNSS):

-   -   Change from baseline in PNSS and physician assessed individual        nasal symptoms at Day 15 (Visit 4).

Pediatric Rhinoconjuntivitis Quality of Life Questionnaire (PRQLQ):

-   -   Change from baseline in individual domains of the PRQLQ at Day        15.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and application of the presentinvention. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments.

All publications, patents, and patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated herein byreference.

1-53. (canceled)
 54. A method of treating allergic rhinitis and/orsymptoms associated therewith in a human in need thereof comprisingnasally administering to the human an effective amount of a fixed-dosepharmaceutical composition comprising mometasone furoate and olopatadineor its salt, in a weight ratio of from about 1:12 to about 1:53, wherein(i) the composition is nasally administered as 1 or 2 sprays pernostril, at least once daily, (ii) the pharmaceutical composition has apH between about 3.3 and about 4.1, and (iii) each spray comprisesolopatadine hydrochloride equivalent to about 600 mcg of olopatadine andabout 25 mcg to about 50 mcg of mometasone furoate
 55. The method ofclaim 54, wherein the composition comprises mometasone furoate andolopatadine or its salt in a weight ratio of about 1:13.3 to about1:26.6.
 56. The method of claim 54, wherein the symptoms are selectedfrom nasal symptoms.
 57. The method of claim 56, wherein the nasalsymptoms are selected from nasal congestion, rhinorrhea, itching andsneezing.
 58. The method of claim 54, wherein the allergic rhinitis isseasonal allergic rhinitis.
 59. The method of claim 54, wherein theallergic rhinitis is perennial allergic rhinitis.
 60. A method oftreating allergic rhinitis in a human in need thereof comprising nasallyadministering to the human an effective amount of a fixed-dosepharmaceutical composition comprising mometasone furoate and olopatadineor its salt, wherein (i) the composition is nasally administered as 1 or2 sprays per nostril of the human at least once daily, (ii) each spraycomprises mometasone furoate and olopatadine or its salt in a weightratio of about 1:5 to about 1:60 (based on the equivalent weight ofolopatadine free base), and (iii) the method provides reduction in atleast one treatment-related adverse effect relative to the use ofolopatadine alone.
 61. The method of claim 60, wherein the compositioncomprises mometasone furoate and olopatadine or its salt in a weightratio of about 1:13.3 to about 1:26.6.
 62. The method of claim 60,wherein the treatment-related adverse effect is epistaxis.
 63. Themethod of claim 60, wherein the symptoms are selected from nasalsymptoms.
 64. The method of claim 63, wherein the nasal symptoms areselected from nasal congestion, rhinorrhea, itching and sneezing. 65.The method of claim 60, wherein the allergic rhinitis is seasonalallergic rhinitis.
 66. The method of claim 60, wherein the allergicrhinitis is perennial allergic rhinitis.
 67. A method of treatingallergic rhinitis and/or symptoms associated therewith in a human inneed thereof comprising nasally administering to the human an effectiveamount of a fixed-dose pharmaceutical composition comprising mometasonefuroate and olopatadine or its salt, in a weight ratio of about 1:12 toabout 1:53, wherein (i) the composition is nasally administered as 1 or2 sprays per nostril, at least once daily, (ii) each spray comprisesolopatadine hydrochloride equivalent to about 600 mcg of olopatadine andabout 25 mcg to about 50 mcg of mometasone furoate, and (iii) thecomposition has a total impurity content of no more than 1.0% afterstorage at about 25° C. and 60% relative humidity for a period of atleast 6 months.
 68. A method of treating one or more symptoms associatedwith allergic rhinitis in a human subject in need thereof comprisingnasally administering twice daily, two sprays per nostril of afixed-dose aqueous pharmaceutical composition comprising mometasonefuroate and olopatadine hydrochloride, wherein (i) the composition has apH between about 3.3 and about 4.1, (ii) each spray comprises about 25mcg of mometasone furoate and about 665 mcg olopatadine hydrochloride,(iii) the composition contains less than 2% of crystallized olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 3 months of storage at 25° C.±2°C. and 60%±5% relative humidity.
 69. The method of claim 68, wherein thecomposition contains less than 2% of crystallized olopatadinehydrochloride, based on the 100% total weight of olopatadinehydrochloride in the composition, after 6 months of storage at 25° C.±2°C. and 60%±5% relative humidity.
 70. A method of treating one or moresymptoms associated with allergic rhinitis in a human subject in needthereof comprising nasally administering twice daily, two sprays pernostril of a fixed-dose aqueous pharmaceutical composition comprisingmometasone furoate and olopatadine hydrochloride, wherein (i) thecomposition has a pH between about 3.3 and about 4.1, (ii) each spraycomprises about 25 mcg of mometasone furoate and about 665 mcgolopatadine hydrochloride, (iii) the composition contains less than 2%of crystallized olopatadine hydrochloride, based on the 100% totalweight of olopatadine hydrochloride in the composition, after 3 monthsof storage at 40° C.±2° C. and 75%±5% relative humidity.
 71. The methodof claim 70, wherein the composition contains less than 2% ofcrystallized olopatadine hydrochloride, based on the 100% total weightof olopatadine hydrochloride in the composition, after 6 months ofstorage at 40° C.±2° C. and 75%±5% relative humidity.